Medical School · Year 2 · Microbiology · includes a quiz and discussion video

Lecture 2: Bacterial Pathogenesis

Unit 2.8: Microbiology

Learning Objectives

By the end of this lecture, students will be able to:

1. Describe the steps of bacterial pathogenesis
2. Explain virulence factors and their mechanisms
3. Describe bacterial toxins and their clinical effects
4. Explain host defense evasion strategies
5. Describe the host response to bacterial infection
6. Explain the clinical manifestations of sepsis

Lecture Outline

I. Steps of Pathogenesis

The study of bacterial pathogenesis seeks to understand how microorganisms cause disease in their hosts. This knowledge forms the foundation for developing preventive measures, diagnostic tools, and therapeutic interventions. The relationship between bacteria and host is complex, involving a series of orchestrated steps that allow certain organisms to overcome host defenses and establish infection. Not all bacteria possess the capabilities needed to cause disease; those that do are termed pathogens, and the specific properties enabling them to cause disease are called virulence factors.

The formal framework for establishing causation between a microorganism and disease was codified by Robert Koch in the 1880s and remains influential today. Koch's postulates stipulate four criteria: the organism must be found in all cases of the disease but absent from healthy individuals; the organism must be isolated from a diseased host and grown in pure culture; the cultured organism must cause the same disease when introduced into a healthy susceptible host; and the organism must be re-isolated from the experimentally infected host. While these postulates revolutionized the study of infectious diseases and remain conceptually important, they have limitations in modern microbiology. Many pathogens cannot be cultured using conventional methods, some organisms cause disease only in humans with no suitable animal model, and certain conditions arise from normal flora when host defenses are compromised. Molecular modifications to Koch's postulates, such as those proposed by Stanley Falkow, focus on demonstrating that specific genes contribute to virulence.

The pathogenic process can be conceptualized as a series of sequential stages, each presenting distinct challenges for the bacterium. Exposure occurs when a susceptible host encounters the pathogen through environmental contact, person-to-person transmission, or other means. Adhesion follows, in which the bacterium attaches to host surfaces using specialized structures called adhesins. Invasion involves penetration into tissues or cells, though some pathogens cause disease without invading. Colonization represents the successful establishment and multiplication of the organism at the infection site. Damage to host tissues may result directly from bacterial factors or indirectly from the host immune response. Finally, the organism may spread locally or disseminate to distant sites, or alternatively be contained and eliminated by host defenses.

The portal of entry profoundly influences which organisms can establish infection and the resulting clinical syndrome. The respiratory tract serves as the entry point for airborne pathogens including Streptococcus pneumoniae, Mycobacterium tuberculosis, and Legionella pneumophila. The gastrointestinal tract is the portal for food and waterborne pathogens such as Salmonella, Shigella, Vibrio cholerae, and Campylobacter. The urogenital tract allows entry of sexually transmitted pathogens including Neisseria gonorrhoeae, Chlamydia trachomatis, and Treponema pallidum, as well as ascending urinary pathogens like uropathogenic Escherichia coli. Skin normally provides an effective barrier, but breaks in the integument allow entry of Staphylococcus aureus, Streptococcus pyogenes, and Clostridium species. Parenteral introduction through bites, needles, or medical devices bypasses normal barriers entirely. The infectious dose, defined as the number of organisms required to establish infection, varies enormously between species and reflects virulence. Shigella species can cause disease with as few as 10 to 100 organisms, reflecting their ability to survive gastric acid and efficiently invade intestinal epithelium. In contrast, Vibrio cholerae requires 10 to the sixth through 10 to the eighth organisms because most are killed by stomach acid before reaching the intestine.

<image>Panel A: Flow diagram illustrating Koch's postulates as four connected steps: diseased host with bacteria identified, isolation of organism into pure culture on a petri dish, inoculation of pure culture into healthy susceptible host resulting in disease, and re-isolation of the same organism from the experimentally infected host, with arrows connecting each step sequentially. Panel B: Sequential stages of bacterial pathogenesis depicted as a timeline showing exposure (contact with pathogen), adhesion (bacterium attaching to epithelial surface), invasion (crossing epithelial barrier), colonization (multiplying bacteria), tissue damage (injured cells), and spread (dissemination through bloodstream or local extension), each stage illustrated with simple cellular diagrams. Panel C: Human body silhouette displaying major portals of entry: respiratory tract (nose and lungs) with aerosol particles, GI tract (mouth to intestines) with contaminated food, urogenital tract with ascending infection arrows, skin with break showing entry point, and parenteral route showing needle or bite introducing organisms directly to bloodstream. Panel D: Bar graph comparing infectious doses of different pathogens on a logarithmic scale, ranging from Shigella at 10-100 organisms (lowest), through Campylobacter at 500-800, Salmonella at 10^5-10^8, to Vibrio cholerae at 10^6-10^8 (highest), with annotations explaining factors affecting dose requirements.</image>

II. Adherence and Colonization

Adhesion to host surfaces represents the critical first step in establishing infection for most bacterial pathogens. Without the ability to attach, bacteria would be swept away by mucociliary clearance, intestinal peristalsis, urinary flow, or other host mechanisms for removing foreign material. The interaction between bacterial adhesins and host cell receptors exhibits remarkable specificity, explaining tissue tropism and why certain pathogens cause disease at particular anatomical sites. This specificity also presents opportunities for therapeutic intervention, as blocking adhesion could prevent infection without selecting for antibiotic resistance.

Bacterial adhesins can be broadly categorized into pilus (fimbrial) and non-pilus (afimbrial) types. Pili, also called fimbriae, are hair-like proteinaceous appendages extending from the bacterial surface that present adhesin molecules at their tips. Type 1 fimbriae found on many Enterobacteriaceae bind to mannose residues on host cells; this binding can be blocked by mannose in a phenomenon called mannose-sensitive adhesion. P fimbriae of uropathogenic Escherichia coli bind to galactose-galactose disaccharides (Gal-Gal) present on uroepithelial cells, explaining the tropism of these strains for the urinary tract. Neisseria gonorrhoeae produces type IV pili essential for initial attachment to urethral epithelium. Non-pilus adhesins are surface proteins that mediate attachment through diverse mechanisms. Filamentous hemagglutinin (FHA) of Bordetella pertussis is a large surface protein mediating attachment to respiratory epithelium. The MSCRAMM (microbial surface components recognizing adhesive matrix molecules) family of Staphylococcus aureus includes proteins binding fibronectin, fibrinogen, and collagen, allowing attachment to extracellular matrix components. Helicobacter pylori expresses BabA adhesin that binds to Lewis b blood group antigen on gastric epithelial cells, contributing to its ability to colonize the stomach.

Biofilms represent a sophisticated form of bacterial colonization with enormous clinical significance. Rather than existing as free-floating planktonic cells, bacteria within biofilms form structured communities attached to surfaces and encased in a self-produced extracellular matrix composed of polysaccharides, proteins, and DNA. Biofilm bacteria exhibit dramatically increased resistance to antibiotics, with minimum inhibitory concentrations often 100 to 1000 times higher than for planktonic cells of the same species. This resistance results from multiple factors: the matrix acts as a physical barrier limiting antibiotic penetration, bacteria in the interior of biofilms exist in a metabolically dormant state less susceptible to antibiotics targeting active processes, and biofilm communities contain persister cells that can survive antibiotic treatment and repopulate the biofilm. Biofilms form on medical devices including intravascular catheters, urinary catheters, endotracheal tubes, prosthetic heart valves, and orthopedic implants. Clinical examples include Pseudomonas aeruginosa biofilms in the airways of cystic fibrosis patients that are essentially impossible to eradicate, Staphylococcus epidermidis biofilms on central venous catheters, and dental plaque composed of complex multispecies biofilm communities.

The normal flora (microbiota) provides a form of colonization resistance that protects against pathogen establishment. Resident bacteria compete with potential pathogens for nutrients and attachment sites, produce antimicrobial substances including bacteriocins and short-chain fatty acids, and stimulate host immune defenses. Disruption of this microbial community, most commonly by antibiotic therapy, eliminates the competitive barrier and allows pathogens to colonize. The most dramatic example is Clostridioides difficile infection, in which antibiotic-mediated disruption of intestinal flora permits overgrowth of this toxin-producing organism, causing antibiotic-associated colitis ranging from mild diarrhea to life-threatening pseudomembranous colitis. The concept of colonization resistance has led to therapeutic approaches including probiotics (administration of beneficial bacteria) and fecal microbiota transplantation for recurrent C. difficile infection.

<image>Panel A: Detailed illustration of bacterial adhesins showing a bacterium with multiple pili (thin hair-like projections) extending to contact a host epithelial cell surface receptor, alongside non-pilus adhesins (surface proteins) directly mediating attachment, with labels identifying type 1 fimbriae, P fimbriae, and MSCRAMM proteins as examples. Panel B: Receptor-adhesin specificity diagram showing three examples: E. coli P pili binding Gal-Gal receptors on urinary epithelium, S. aureus fibronectin-binding protein attaching to extracellular matrix, and H. pylori BabA binding Lewis b antigen on gastric mucosa, each with molecular detail of the interaction. Panel C: Cross-section of mature biofilm showing the layered structure with bacteria in microcolonies embedded within extracellular polymeric matrix, water channels penetrating the structure, planktonic bacteria being released from the surface, and attachment to an underlying substrate (catheter surface), with labels indicating the protective matrix and metabolically dormant interior bacteria. Panel D: Colonization resistance illustration showing a healthy intestine with diverse normal flora preventing pathogen attachment (depicted as pathogens being repelled), contrasted with an antibiotic-treated intestine showing depleted flora and C. difficile overgrowth with toxin production, demonstrating the protective effect of normal microbiota.</image>

III. Invasion and Tissue Penetration

Following adhesion, many bacterial pathogens must invade host tissues to cause disease. Invasion involves crossing epithelial barriers, penetrating basement membranes, and potentially entering and surviving within host cells. This process requires sophisticated molecular machinery that has evolved to exploit host cellular processes. Some pathogens remain entirely extracellular, causing disease through toxin production or triggering inflammatory responses, while others are obligate or facultative intracellular pathogens that must enter host cells to survive and replicate.

Invasins are bacterial proteins that directly mediate entry into host cells by binding to specific host cell receptors and triggering internalization. Yersinia species produce an outer membrane protein called invasin that binds to beta-1 integrins on M cells of the intestinal Peyer's patches, promoting uptake of the bacteria. Listeria monocytogenes produces two key invasins: internalin A (InlA) binds E-cadherin on epithelial cells, while internalin B (InlB) binds the hepatocyte growth factor receptor c-Met. The specificity of InlA for human E-cadherin (but not mouse E-cadherin) explains why mice are not natural hosts for Listeria and why transgenic mice expressing human E-cadherin are required for modeling intestinal listeriosis.

Two major mechanisms describe how invasive bacteria enter non-phagocytic host cells. The trigger mechanism, employed by Salmonella and Shigella, involves injection of bacterial effector proteins directly into the host cell cytoplasm through a type III secretion system, essentially a molecular syringe. These effectors manipulate host cell signaling pathways, particularly those controlling the actin cytoskeleton, causing dramatic membrane ruffling that engulfs the bacterium in a process resembling macropinocytosis. The zipper mechanism, used by Listeria and Yersinia, involves tight binding between bacterial invasins and host cell receptors that progressively zip the host cell membrane around the bacterium, internalizing it in a tightly fitting vacuole. Both mechanisms ultimately deliver bacteria into membrane-bound compartments within the host cell, but the resulting vacuoles have different properties and fates.

Once inside host cells, intracellular pathogens must avoid destruction in the phagolysosomal pathway. Different bacteria have evolved distinct strategies to accomplish this. Listeria monocytogenes and Shigella species escape from the phagosome into the cytoplasm using pore-forming toxins (listeriolysin O and IpaB, respectively), where they are protected from lysosomal enzymes and can replicate freely. Both organisms also polymerize host cell actin to propel themselves through the cytoplasm and into adjacent cells, spreading without exposure to extracellular antibodies or complement. Mycobacterium tuberculosis and Legionella pneumophila prevent phagosome-lysosome fusion, residing in modified vacuoles that do not acquire lysosomal enzymes. Salmonella enterica survives and replicates within the acidified phagolysosome-like compartment called the Salmonella-containing vacuole (SCV), using effectors injected via a second type III secretion system (SPI-2) to remodel the vacuole and resist antimicrobial factors. In addition to invasins, bacteria produce various tissue-degrading enzymes that facilitate spread through tissues. Hyaluronidase degrades hyaluronic acid in connective tissue ground substance, collagenase breaks down collagen fibers, and streptokinase and staphylokinase activate plasminogen to dissolve fibrin clots. DNase allows bacteria to escape from neutrophil extracellular traps (NETs), web-like structures of DNA and antimicrobial proteins that neutrophils release to trap and kill extracellular bacteria.

<image>Panel A: Comparison of trigger and zipper invasion mechanisms side by side: trigger mechanism showing a bacterium injecting effector proteins via type III secretion system causing dramatic actin rearrangement and membrane ruffling to engulf the bacterium (Salmonella), and zipper mechanism showing tight sequential receptor-ligand binding progressively drawing host cell membrane around the bacterium in a close-fitting manner (Listeria). Panel B: Type III secretion system detailed diagram showing the needle apparatus spanning bacterial inner membrane, periplasm, outer membrane, and penetrating the host cell membrane, with effector proteins being injected directly into the host cytoplasm, labeled with structural components (basal body, needle, translocon). Panel C: Intracellular survival strategies illustrated in a host cell: one bacterium (Listeria) escaping from phagosome via listeriolysin O pore formation and moving through cytoplasm on actin tail, another bacterium (Mycobacterium) residing in a modified vacuole that has not fused with lysosomes shown nearby, and a third bacterium (Salmonella) in an acidified vacuole with modified properties, each strategy labeled. Panel D: Tissue-degrading enzymes and their actions depicted around a focus of bacterial infection: hyaluronidase breaking down ground substance, collagenase degrading collagen fibers, kinases dissolving fibrin clots, and DNase allowing escape from neutrophil extracellular traps (shown as web-like structures being degraded), facilitating bacterial spread through tissue.</image>

IV. Bacterial Toxins - A-B Toxins

Bacterial toxins are among the most potent biological substances known and serve as major virulence factors for many important pathogens. The A-B toxins constitute a large and diverse family characterized by a common structural organization: a binding (B) component that attaches to specific receptors on host cell surfaces, and an enzymatically active (A) component that enters the cell and disrupts normal cellular functions. This modular design allows extraordinary specificity in targeting particular cell types and executing defined biochemical modifications that produce characteristic disease manifestations.

The A-B toxin architecture reflects a requirement for toxins to access intracellular targets while being produced and secreted extracellularly. The B subunit or subunits recognize specific glycolipid or glycoprotein receptors on host cell surfaces, providing exquisite target cell specificity. Following receptor binding, the toxin is internalized by receptor-mediated endocytosis. Within the endosome, conformational changes triggered by acidification allow the A subunit (or A fragment) to translocate across the endosomal membrane into the cytoplasm, either directly or after retrograde transport through the Golgi and endoplasmic reticulum. Once in the cytoplasm, the A subunit carries out its enzymatic activity, typically with extremely high efficiency such that a single molecule can produce cell death. Many A-B toxins require proteolytic cleavage for activation, either by host proteases or bacterial proteases, liberating the A subunit from the B subunit while maintaining association through disulfide bonds that are subsequently reduced in the cytoplasm.

Diphtheria toxin, produced by lysogenized strains of Corynebacterium diphtheriae carrying the beta prophage, exemplifies the A-B toxin mechanism. The B fragment binds to heparin-binding epidermal growth factor precursor (HB-EGF) on host cell surfaces, leading to receptor-mediated endocytosis. Acidification of the endosome causes conformational changes that allow the translocation domain to insert into the membrane and facilitate transfer of the A fragment to the cytoplasm. The A fragment catalyzes ADP-ribosylation of elongation factor 2 (EF-2), specifically modifying a unique amino acid called diphthamide. This modification inactivates EF-2, halting protein synthesis and causing cell death. Remarkably, a single toxin molecule can kill a cell because each A fragment can modify multiple EF-2 molecules. Clinical manifestations include the characteristic pharyngeal pseudomembrane composed of dead epithelial cells, fibrin, and bacteria, as well as myocarditis and neuropathies resulting from systemic toxin effects.

Cholera toxin produced by Vibrio cholerae causes the profuse watery diarrhea characteristic of cholera through a different enzymatic mechanism. The toxin consists of one A subunit associated with a pentameric ring of five B subunits. The B pentamer binds to GM1 ganglioside on intestinal epithelial cell surfaces with remarkable avidity due to multivalent binding. Following internalization and retrograde transport, the A1 subunit ADP-ribosylates the alpha subunit of the stimulatory G protein (Gsα), locking it in the active GTP-bound state. This permanently activates adenylyl cyclase, causing uncontrolled elevation of intracellular cyclic AMP. In intestinal epithelial cells, elevated cAMP activates chloride channels (CFTR) in the apical membrane, causing massive chloride secretion into the intestinal lumen. Sodium and water follow osmotically, producing the characteristic rice-water stool that can exceed 20 liters per day and cause fatal dehydration within hours if untreated. The heat-labile toxin (LT) of enterotoxigenic Escherichia coli (ETEC) is structurally and functionally nearly identical to cholera toxin and produces traveler's diarrhea by the same mechanism.

<image>Panel A: General A-B toxin structure and mechanism showing a complete toxin with A subunit (labeled as enzymatic component) and B subunit(s) (labeled as binding component), binding to a specific cell surface receptor, internalization into an endosome, acid-induced conformational change, translocation of the A subunit across the membrane into the cytoplasm, and enzymatic action on the intracellular target, with each step numbered and described. Panel B: Diphtheria toxin mechanism in detail showing B fragment binding to HB-EGF receptor on a cell, endocytosis, acidification causing T domain insertion and A fragment translocation, A fragment catalyzing ADP-ribosylation of EF-2 (shown with NAD+ as substrate and nicotinamide as product), ribosome stalled during translation due to inactive EF-2, and resultant cell death, with clinical images of pharyngeal pseudomembrane. Panel C: Cholera toxin mechanism showing the AB5 structure with pentameric B ring binding to five GM1 gangliosides on intestinal epithelial cell surface, internalization and retrograde transport through ER, A1 subunit ADP-ribosylating Gsα protein, locked-active adenylyl cyclase producing abundant cAMP, activated CFTR chloride channels causing chloride and water secretion into intestinal lumen. Panel D: Comparison of other major A-B toxins displayed in a grid format showing tetanus toxin and botulinum toxin (both cleaving SNARE proteins but at different locations in the nervous system with opposite clinical effects), pertussis toxin (ADP-ribosylating Gi), Shiga toxin (cleaving 28S rRNA), and exotoxin A of Pseudomonas (ADP-ribosylating EF-2 like diphtheria), each with target, mechanism, and clinical effect briefly noted.</image>

V. Bacterial Toxins - Other Types

Beyond the A-B toxin family, bacteria produce diverse toxins acting through other mechanisms to damage host tissues and subvert host defenses. These include superantigens that cause massive immune activation, membrane-damaging toxins that directly lyse host cells, cytotoxins targeting specific cell populations, and neurotoxins that disrupt neural transmission. Understanding these toxin categories illuminates the pathogenesis of diseases ranging from toxic shock syndrome to gas gangrene to paralytic syndromes.

Superantigens represent a unique class of toxins that cause disease by hyperactivating the adaptive immune system rather than by directly damaging cells. These proteins bind simultaneously to major histocompatibility complex class II molecules on antigen-presenting cells and to specific variable regions of the T cell receptor beta chain, crosslinking these molecules outside of the normal antigen-binding groove. This interaction bypasses normal antigen processing and presentation, and because up to 20 percent of T cells may express a particular V-beta region, superantigens can activate an enormous fraction of the T cell population. The resulting massive T cell proliferation triggers a cytokine storm with release of interleukin-2, tumor necrosis factor-alpha, interleukin-1, and interferon-gamma at levels causing systemic toxicity. Toxic shock syndrome toxin-1 (TSST-1) produced by certain strains of Staphylococcus aureus causes staphylococcal toxic shock syndrome, classically associated with tampon use but also occurring with wound infections. The streptococcal pyrogenic exotoxins (Spe proteins) produced by Streptococcus pyogenes cause streptococcal toxic shock syndrome. Clinical features of superantigen-mediated toxic shock include high fever, diffuse erythematous rash (sometimes with subsequent desquamation), hypotension, and multiorgan dysfunction.

Membrane-damaging toxins directly attack host cell membranes, causing cell lysis and tissue destruction. Pore-forming toxins constitute the largest group, assembling into oligomeric ring structures that insert into the lipid bilayer and create transmembrane channels. Streptolysin O produced by Streptococcus pyogenes and related cholesterol-dependent cytolysins (including perfringolysin O from Clostridium perfringens and listeriolysin O from Listeria monocytogenes) bind membrane cholesterol and oligomerize to form large pores, causing osmotic lysis. Alpha-hemolysin of Staphylococcus aureus forms smaller pores but efficiently kills leukocytes and other cells. Phospholipases represent another category of membrane-damaging toxins that enzymatically degrade membrane phospholipids. Clostridium perfringens alpha-toxin (phospholipase C, also called lecithinase) hydrolyzes phosphatidylcholine, a major membrane phospholipid, causing cell destruction that contributes to the tissue necrosis of gas gangrene.

Certain toxins specifically target particular cell populations, producing characteristic clinical syndromes. Shiga toxin produced by Shigella dysenteriae serotype 1 and Shiga-like toxins (also called verotoxins) produced by enterohemorrhagic Escherichia coli (EHEC, particularly O157:H7) are A-B toxins that cleave ribosomal RNA, halting protein synthesis. These toxins preferentially damage vascular endothelial cells, particularly in the kidney, causing thrombotic microangiopathy that manifests as hemolytic uremic syndrome (HUS) with microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Panton-Valentine leukocidin (PVL) of Staphylococcus aureus specifically targets and destroys neutrophils, contributing to the virulence of community-acquired MRSA strains that cause severe necrotizing pneumonia and skin infections. The neurotoxins of Clostridium tetani (tetanospasmin) and Clostridium botulinum (botulinum toxin) are A-B toxins that target the nervous system with opposite clinical effects despite similar mechanisms. Both toxins are zinc metalloproteases that cleave SNARE proteins essential for synaptic vesicle fusion and neurotransmitter release. Tetanus toxin is transported retrograde along peripheral nerves to the spinal cord, where it blocks release of inhibitory neurotransmitters (glycine and GABA) from interneurons, causing unopposed motor neuron firing and spastic paralysis with characteristic risus sardonicus and opisthotonus. Botulinum toxin acts at the neuromuscular junction, blocking acetylcholine release and causing flaccid paralysis with cranial nerve involvement followed by descending weakness.

<image>Panel A: Superantigen mechanism illustrated showing an antigen-presenting cell (macrophage or dendritic cell) with MHC class II molecule and a T cell with T cell receptor being bridged by a superantigen molecule binding outside the normal peptide-binding groove, direct crosslinking activating the T cell without need for processed antigen, resulting in massive cytokine release (depicted as abundant TNF-alpha, IL-1, IL-2, IFN-gamma molecules) causing fever, hypotension, rash, and multiorgan damage. Panel B: Pore-forming toxin mechanism showing monomeric toxin proteins binding to cell membrane, oligomerization into a ring structure, insertion through the lipid bilayer to create a transmembrane pore, influx of calcium and water with efflux of potassium and ATP, leading to osmotic cell lysis, with examples labeled (streptolysin O, alpha-hemolysin). Panel C: Comparison of tetanus and botulinum neurotoxin mechanisms showing both toxins being taken up at peripheral nerve terminals: tetanus toxin undergoing retrograde axonal transport to spinal cord interneurons where it blocks inhibitory neurotransmitter release causing uncontrolled motor neuron firing (spastic paralysis); botulinum toxin acting locally at the neuromuscular junction blocking acetylcholine release (flaccid paralysis), with characteristic clinical postures illustrated for each. Panel D: Shiga toxin and hemolytic uremic syndrome pathway showing the toxin binding to globotriaosylceramide (Gb3) receptor on endothelial cells, internalization, A subunit cleaving 28S rRNA to halt protein synthesis, endothelial damage leading to platelet aggregation and microthrombi formation, red blood cells being sheared as they pass through damaged vessels (fragmented schistocytes), resulting in the HUS triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury.</image>

VI. Endotoxin and Sepsis

Endotoxin, the lipopolysaccharide (LPS) component of the gram-negative bacterial outer membrane, triggers a distinct pathophysiological cascade that can progress from beneficial inflammation to life-threatening septic shock. Unlike protein exotoxins that are secreted by living bacteria and have specific enzymatic activities, endotoxin is released when bacteria die or when the outer membrane is disrupted, and its effects result from activation of host innate immune responses. Understanding the endotoxin-sepsis pathway is essential for managing one of the most common and deadly conditions in intensive care medicine.

Lipopolysaccharide consists of three structural regions with distinct properties and functions. Lipid A is the membrane-anchored component and constitutes the toxic moiety responsible for the biological effects of endotoxin. Its structure is highly conserved across gram-negative species, consisting of a phosphorylated glucosamine disaccharide with attached fatty acid chains. The core polysaccharide is a branched oligosaccharide that is relatively conserved within bacterial groups. The O antigen (O polysaccharide) is a highly variable repeating oligosaccharide chain extending outward from the cell surface that is used for serotyping and can be modified to evade host immunity. While the carbohydrate portions of LPS can be antigenic, it is Lipid A that activates innate immune receptors and initiates the inflammatory cascade.

The host recognition of endotoxin involves a sophisticated receptor complex that evolved to detect this conserved pathogen-associated molecular pattern. LPS-binding protein (LBP), an acute phase reactant in serum, binds free LPS and facilitates its transfer to CD14, a glycosylphosphatidylinositol-anchored protein on monocytes and macrophages (or soluble CD14 for cells lacking membrane CD14). CD14 transfers LPS to the signaling receptor complex consisting of Toll-like receptor 4 (TLR4) and MD-2, a small accessory protein that physically binds LPS. The LPS-MD-2-TLR4 complex dimerizes and initiates intracellular signaling through adapter proteins, primarily MyD88, activating transcription factors including NF-kappaB. This results in transcription and release of proinflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and interleukin-6 (IL-6), which mediate the systemic effects of endotoxin.

The pathophysiology of sepsis results from the host inflammatory response to infection spiraling out of control. When the cytokine response is appropriately calibrated, it helps eliminate pathogens and resolve infection. However, excessive or dysregulated inflammation produces systemic effects that themselves become life-threatening. TNF-alpha and IL-1 induce fever through their action on the hypothalamus, cause vasodilation and increased vascular permeability leading to hypotension and edema, and activate endothelial cells promoting coagulation. The coagulation cascade is activated while anticoagulant mechanisms are suppressed, leading to disseminated intravascular coagulation (DIC) with widespread microvascular thrombosis and paradoxical bleeding due to consumption of clotting factors. Complement activation amplifies inflammation. Tissue hypoperfusion from hypotension and microvascular obstruction causes cellular hypoxia and organ dysfunction. The clinical progression follows a continuum: systemic inflammatory response syndrome (SIRS) denotes the systemic inflammatory state characterized by fever or hypothermia, tachycardia, tachypnea, and abnormal white blood cell count. Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Septic shock is a subset of sepsis with circulatory and cellular dysfunction associated with hypotension requiring vasopressors and elevated lactate despite adequate fluid resuscitation. Mortality in septic shock ranges from 20 to 50 percent even with optimal care.

<image>Panel A: Lipopolysaccharide structure diagram showing the complete molecule anchored in the outer membrane, with Lipid A embedded in the lipid bilayer (labeled as the toxic component, showing the glucosamine backbone with phosphate groups and fatty acid chains), the core polysaccharide as a branched structure (labeled as relatively conserved), and the O antigen as a long repeating oligosaccharide chain extending outward (labeled as variable, used for serotyping). Panel B: LPS recognition pathway showing the sequential steps: free LPS in bloodstream, LPS-binding protein capturing LPS, transfer to CD14 on macrophage surface, transfer to TLR4-MD-2 complex, receptor dimerization, intracellular signaling through MyD88 and TRAF6, activation of NF-kappaB transcription factor, and production of TNF-alpha, IL-1, and IL-6 cytokines. Panel C: Sepsis pathophysiology cascade flowchart showing gram-negative bacteria releasing LPS, macrophage activation producing cytokines, systemic effects branching to: vasodilation and capillary leak (causing hypotension), endothelial activation (causing DIC), and metabolic derangement (causing organ dysfunction), with feedback loops amplifying the response, ultimately leading to multiorgan failure. Panel D: Clinical sepsis continuum illustrated as a severity progression: initial infection, SIRS (depicting patient with fever, tachycardia, tachypnea), sepsis (showing organ dysfunction markers - elevated creatinine, bilirubin, altered mental status), severe sepsis with hypotension responding to fluids, and septic shock with vasopressor requirement and elevated lactate, with mortality percentages indicated at each stage.</image>

VII. Immune Evasion Strategies

Successful pathogens have evolved sophisticated mechanisms to evade, subvert, or resist host immune defenses. These immune evasion strategies are essential virulence factors that distinguish pathogens from the many bacteria that are rapidly eliminated by innate immunity. Understanding these mechanisms reveals the ongoing evolutionary arms race between microbes and hosts and identifies potential therapeutic targets to tip the balance toward host defense.

The bacterial capsule represents one of the most important and widespread immune evasion structures. Capsules are polysaccharide (or occasionally polypeptide) layers external to the cell wall that inhibit phagocytosis through multiple mechanisms. The hydrophilic, negatively charged capsule creates a physical barrier that prevents complement components and antibodies from reaching the bacterial surface where they could promote opsonization. Capsules also mask underlying structures that would otherwise activate complement via the alternative pathway. Some capsular polysaccharides directly inhibit complement activation, and others mimic host polysaccharides, reducing immunogenicity. The importance of capsules is demonstrated by the dramatically increased virulence of encapsulated versus non-encapsulated strains: encapsulated Streptococcus pneumoniae causes invasive disease while non-encapsulated strains are usually limited to mucosal colonization. The clinical significance of capsules is reflected in the success of conjugate vaccines targeting capsular polysaccharides of Haemophilus influenzae type b, Streptococcus pneumoniae, and Neisseria meningitidis.

Complement evasion involves diverse mechanisms beyond capsular inhibition. Some bacteria produce proteases that cleave complement components, directly inactivating them. Staphylococcus aureus secretes SCIN (staphylococcal complement inhibitor) that blocks C3 convertase activity. Many pathogens recruit host complement regulatory proteins to their surfaces; for example, Neisseria gonorrhoeae binds factor H, which normally protects host cells from complement attack, thereby appearing as "self" to the complement system. Bacteria can also modify their surface structures to reduce complement deposition; lengthening of the O antigen polysaccharide chain in LPS sterically inhibits membrane attack complex insertion into the outer membrane.

Antigenic variation allows pathogens to evade adaptive immune responses by changing their surface antigens faster than the immune system can respond. Phase variation involves on-off switching of gene expression, often through slipped-strand mispairing during DNA replication, allowing bacteria to present different surface structures in different environmental conditions. Neisseria species use phase variation to toggle pili and other surface proteins on and off. True antigenic variation involves changing the expressed variant of a gene from a repertoire of variants in the genome. Borrelia species cause relapsing fever by sequentially expressing different variable membrane proteins (VMPs) from a large library of silent genes, producing recurring waves of bacteremia as each new variant evades antibodies against the previous one. Trypanosoma brucei (a eukaryotic parasite) uses a similar mechanism with variant surface glycoproteins. Serotype switching, as seen in Streptococcus pneumoniae with its over 90 capsular serotypes and Salmonella with numerous O and H antigen types, allows different strains to evade immunity generated against previously encountered serotypes.

Intracellular survival within host cells provides a protected niche hidden from antibodies and complement. As discussed earlier, different pathogens employ distinct strategies: escape from the phagosome into the cytoplasm (Listeria, Shigella), prevention of phagosome-lysosome fusion (Mycobacterium, Legionella), or survival within the hostile phagolysosome environment (Salmonella, Coxiella). Intracellular bacteria must also evade cell-autonomous immunity, including autophagy that can capture cytoplasmic bacteria and inflammasome activation that can trigger pyroptotic cell death. These pathogens often modulate host cell signaling to promote their own survival while preventing host responses that would destroy them.

<image>Panel A: Capsule antiphagocytic mechanism showing an encapsulated bacterium (with thick polysaccharide layer) versus non-encapsulated bacterium approaching a macrophage, demonstrating how the capsule prevents complement C3b deposition and antibody binding, blocks recognition by complement receptors and Fc receptors, and ultimately prevents phagocytosis, while the non-encapsulated bacterium is readily opsonized and engulfed. Panel B: Complement evasion strategies illustrated as multiple mechanisms: bacterial protease cleaving C3 or C5 complement components, recruitment of factor H to the bacterial surface (shown binding to bacterial protein and remaining active as a complement regulator), SCIN blocking C3 convertase activity, and extended O antigen chains sterically preventing MAC insertion into the outer membrane. Panel C: Antigenic variation mechanisms depicted for three examples: phase variation showing a genetic switch turning pilus expression on or off through slipped-strand mispairing, gene conversion showing silent gene cassettes being copied into an expression locus producing different VMPs (Borrelia), and serotype diversity showing multiple pneumococcal capsule types representing distinct serotypes. Panel D: Intracellular survival strategies within a macrophage showing three distinct compartments: Listeria escaping phagosome via listeriolysin O pore formation and replicating in cytoplasm while evading autophagy, Mycobacterium residing in a modified phagosome that fails to fuse with lysosome due to bacterial interference with Rab proteins, and Coxiella thriving within the acidified phagolysosome with adaptations to survive the harsh environment.</image>

VIII. Host Response to Infection

The host response to bacterial infection encompasses both innate immunity, providing immediate but non-specific defense, and adaptive immunity, delivering specific and long-lasting protection. These systems work in concert, with innate responses containing initial infection while adaptive responses develop, and with innate signals shaping the character of adaptive immunity. The outcome of infection depends on the balance between bacterial virulence factors and host defense mechanisms, and in many cases, disease manifestations result as much from the host response as from direct bacterial damage.

Innate immunity provides the first line of defense and includes physical and chemical barriers as well as cellular and molecular effector mechanisms. Physical barriers include the skin and mucous membranes, which prevent bacterial access to underlying tissues. Chemical defenses include lysozyme in tears and saliva that degrades peptidoglycan, defensins (antimicrobial peptides) secreted by epithelia, and gastric acid that kills most ingested bacteria. The mucociliary escalator continuously sweeps particles and microbes out of the respiratory tract. When bacteria breach these barriers, they encounter phagocytic cells including neutrophils and macrophages. Neutrophils are rapidly recruited to infection sites and kill bacteria through oxidative burst (reactive oxygen species production), antimicrobial peptides, and degranulation of enzymes into phagolysosomes. Macrophages are tissue-resident cells that phagocytose bacteria and also serve as sentinels, releasing cytokines that recruit additional immune cells and initiate inflammation. The complement system consists of serum proteins that become activated on microbial surfaces, promoting opsonization (C3b coating), direct lysis (membrane attack complex), and inflammation (anaphylatoxins C3a and C5a).

Recognition of bacteria by the innate immune system relies on pattern recognition receptors (PRRs) that detect conserved microbial structures called pathogen-associated molecular patterns (PAMPs). Toll-like receptors (TLRs) on cell surfaces and in endosomes recognize diverse bacterial components: TLR4 recognizes LPS, TLR2 recognizes lipoteichoic acid, peptidoglycan, and lipoproteins, TLR5 recognizes flagellin, and TLR9 recognizes unmethylated CpG DNA motifs. Cytoplasmic receptors including NOD1 and NOD2 detect peptidoglycan fragments that access the cytoplasm. PRR activation triggers signaling cascades leading to cytokine production, inflammation, and activation of antimicrobial responses. This system allows rapid response to infection without requiring prior exposure or antigen-specific recognition.

Adaptive immunity develops over days to weeks following infection but provides highly specific and durable protection. B cells produce antibodies that neutralize toxins, opsonize bacteria for enhanced phagocytosis, and activate complement via the classical pathway. Secretory IgA in mucosal secretions prevents bacterial adhesion to epithelial surfaces. CD4+ helper T cells coordinate the immune response through cytokine secretion: Th1 cells produce interferon-gamma that activates macrophages to kill intracellular bacteria, while Th17 cells produce IL-17 that recruits neutrophils. CD8+ cytotoxic T lymphocytes recognize and kill host cells infected with intracellular bacteria, exposing the pathogens to extracellular defenses. Memory cells generated during primary infection provide long-lasting protection against reinfection, the basis for vaccination.

While immune responses are generally protective, excessive or misdirected immunity can cause immunopathology. Septic shock results from overwhelming systemic inflammation triggered by PAMPs. Post-infectious immune-mediated diseases include acute rheumatic fever, where antibodies against streptococcal M protein cross-react with cardiac tissue (molecular mimicry), and post-streptococcal glomerulonephritis, where immune complexes deposit in glomeruli. Granulomas in tuberculosis represent a double-edged sword: they contain the infection preventing dissemination but cause tissue destruction and may reactivate decades later. Understanding immunopathology is essential for managing infectious diseases and their sequelae.

<image>Panel A: Innate immune defenses illustration showing layered protection: outermost physical barriers (intact skin, mucous membranes with mucus layer and cilia), chemical defenses (lysozyme, defensins, acid), cellular defenses (neutrophils with phagocytosis and oxidative burst, macrophages with phagocytosis and cytokine release), and complement cascade (showing C3b opsonization, MAC formation, and anaphylatoxin release). Panel B: Pattern recognition receptor (PRR) signaling diagram showing a macrophage with various receptors recognizing bacterial components: TLR4 on cell surface binding LPS, TLR2 binding lipoteichoic acid and lipoproteins, TLR5 binding flagellin, TLR9 in endosome binding bacterial DNA, NOD2 in cytoplasm binding muramyl dipeptide, all converging on NF-kappaB activation and cytokine production. Panel C: Adaptive immune response to bacterial infection showing antigen-presenting cell (dendritic cell) presenting bacterial peptides to CD4+ T cells, which differentiate into Th1 cells (producing IFN-gamma to activate macrophages) and Th17 cells (producing IL-17 to recruit neutrophils), B cells receiving T cell help and differentiating into plasma cells producing antibodies for neutralization and opsonization, and CD8+ T cells killing infected host cells. Panel D: Immunopathology examples depicted in three panels: molecular mimicry in rheumatic fever showing anti-streptococcal antibodies cross-reacting with cardiac myocytes, immune complex deposition in post-streptococcal glomerulonephritis showing antibody-antigen complexes in glomerular capillary loops with complement activation, and tuberculosis granuloma showing organized structure of macrophages, epithelioid cells, giant cells, and surrounding lymphocytes containing but also damaging lung tissue.</image>

IX. Types of Infection

Bacterial infections manifest in diverse patterns depending on the pathogen, host factors, and site of infection. Classifying infections along several axes, including local versus systemic extent, acute versus chronic duration, primary versus opportunistic pathogen type, and community versus healthcare-associated acquisition, provides a framework for understanding clinical presentations and guiding management decisions. These classifications are not mutually exclusive, and individual infections may be characterized by multiple descriptors.

The anatomical extent of infection distinguishes localized infections that remain confined to a specific site from systemic infections that spread throughout the body. Local infections include superficial skin infections like impetigo, localized abscesses where bacteria are walled off by inflammatory tissue, and organ-specific infections like uncomplicated cystitis. Even local infections trigger systemic inflammatory responses, but the infection itself remains contained. Invasive infections spread beyond the initial site into normally sterile body spaces: cellulitis extends through soft tissue planes, osteomyelitis reaches bone, and peritonitis indicates infection of the peritoneal cavity. Bacteremia denotes the presence of viable bacteria in the bloodstream, which may be transient (as occurs briefly after dental procedures) or sustained. Septicemia implies bacteria actively multiplying in the blood, though this term is often used loosely. Disseminated or metastatic infections occur when bloodborne bacteria seed distant sites, as in infective endocarditis where cardiac vegetations shower bacteria throughout the circulation.

The time course of infection ranges from acute to chronic. Acute infections develop rapidly over days to weeks, produce intense inflammatory responses, and typically resolve with elimination of the pathogen or death of the host. Examples include bacterial pneumonia, urinary tract infections, and bacterial meningitis. Chronic infections persist for months to years, often because the pathogen evades immune clearance or resides in protected niches. Tuberculosis may persist for a lifetime, with periods of latency punctuated by reactivation. Chronic osteomyelitis involves bacteria sequestered within necrotic bone inaccessible to antibiotics and immune cells. Latent infections represent a special case where the pathogen persists in a dormant state without causing active disease; Mycobacterium tuberculosis can remain latent for decades in granulomas before reactivating. Carrier states involve asymptomatic colonization with a pathogen that can be transmitted to others; the most famous example is Typhoid Mary, an asymptomatic Salmonella typhi carrier who infected dozens of people as a cook.

Primary pathogens cause disease in previously healthy individuals with intact immune defenses, possessing virulence factors sufficient to overcome normal host resistance. Examples include Streptococcus pyogenes, Neisseria meningitidis, and Mycobacterium tuberculosis. Opportunistic pathogens cause disease primarily in hosts with compromised defenses, including immunosuppressed patients, those with breached physical barriers, or those with altered normal flora. Pseudomonas aeruginosa rarely causes disease in healthy individuals but is a major pathogen in neutropenic patients, burn victims, and those with cystic fibrosis. Candida albicans is a normal commensal that causes invasive disease when immune defenses are impaired or after antibiotic disruption of bacterial flora. Healthcare-associated infections (HAIs), previously termed nosocomial infections, are acquired in healthcare settings at least 48 hours after admission. These infections often involve antibiotic-resistant organisms including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), and extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae. Device-associated infections involving central venous catheters, urinary catheters, and ventilators account for a substantial proportion of HAIs and typically involve biofilm formation.

<image>Panel A: Local versus systemic infection illustrated with a human body outline showing local infection as a contained abscess with surrounding inflammation (cross-section showing walled-off cavity with bacteria, neutrophils, and fibrous wall), contrasted with systemic infection showing bacteria entering the bloodstream from the original focus and disseminating to multiple organs (brain, lungs, kidneys, liver) via the circulation. Panel B: Time course of infection graph showing acute infection curve (rapid rise to peak then decline over days to weeks), chronic infection curve (prolonged elevated levels over months to years), latent infection pattern (initial infection controlled then dormant period then reactivation spike), and carrier state (low persistent bacterial burden without symptoms), each with representative diseases labeled. Panel C: Primary versus opportunistic pathogen comparison showing a healthy host successfully fighting off opportunistic pathogen (Pseudomonas) but developing disease from primary pathogen (M. tuberculosis), contrasted with immunocompromised host (neutropenic, on immunosuppressants) developing disease from both opportunistic and primary pathogens, illustrating host defense as the key variable. Panel D: Healthcare-associated infection sources depicted in a hospital room setting showing central venous catheter (bloodstream infection), urinary catheter (catheter-associated UTI), ventilator (ventilator-associated pneumonia), and surgical wound (surgical site infection), with common pathogens labeled at each site (MRSA, VRE, Pseudomonas, ESBL E. coli).</image>

X. Clinical Manifestations

The clinical manifestations of bacterial infection reflect both direct microbial effects and the host inflammatory response. Recognizing the signs and symptoms of infection, understanding their pathophysiological basis, and correlating clinical findings with laboratory data are essential skills for diagnosing and managing infectious diseases. While modern medicine relies heavily on laboratory and imaging studies, clinical assessment remains fundamental, particularly for early recognition of serious infections when rapid intervention is most beneficial.

Fever is the most common and characteristic manifestation of bacterial infection, resulting from the resetting of the hypothalamic thermoregulatory set point. Exogenous pyrogens, most notably LPS (endotoxin), stimulate monocytes and macrophages to produce endogenous pyrogens including interleukin-1, interleukin-6, and tumor necrosis factor-alpha. These cytokines act on the hypothalamus to induce cyclooxygenase-2 (COX-2), leading to prostaglandin E2 (PGE2) production. PGE2 raises the thermoregulatory set point, causing the body to generate and conserve heat through shivering and vasoconstriction until the new set point is reached. Moderate fever may benefit the host by inhibiting growth of some pathogens and enhancing certain immune functions. However, high fever increases metabolic demands, and extreme hyperthermia can cause tissue damage. The pattern of fever, including continuous, remittent, intermittent, or relapsing patterns, may provide diagnostic clues in certain infections.

The cardinal signs of inflammation, described since antiquity, reflect local vascular and cellular responses to infection. Rubor (redness) results from vasodilation of arterioles supplying the affected area, increasing blood flow. Calor (heat) similarly reflects increased blood flow bringing warm central blood to peripheral tissues. Tumor (swelling) results from increased vascular permeability allowing plasma proteins and fluid to leak into the extravascular space. Dolor (pain) is caused by tissue pressure from edema, direct stimulation of sensory nerves by inflammatory mediators including prostaglandins and bradykinin, and sensitization of nociceptors. Functio laesa (loss of function) results from pain, swelling, and tissue damage. While these signs indicate infection, they are not specific and can occur with any cause of inflammation.

Laboratory findings help confirm infection and guide therapy. Leukocytosis (elevated white blood cell count) with neutrophilia is characteristic of bacterial infections, though certain infections (notably typhoid fever and brucellosis) cause leukopenia. A left shift refers to increased immature neutrophils (bands) in peripheral blood, indicating accelerated marrow release in response to infection. Acute phase reactants including C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are elevated in infection and inflammation but lack specificity. Procalcitonin, a prohormone of calcitonin, rises more specifically in bacterial infection than in viral infection or non-infectious inflammation, making it useful for distinguishing bacterial from viral illness and for guiding antibiotic therapy. Serum lactate elevation indicates tissue hypoperfusion and anaerobic metabolism, serving as a marker of sepsis severity. Organ-specific manifestations reflect the site of infection: respiratory infections produce cough, dyspnea, and infiltrates on imaging; urinary infections cause dysuria, frequency, and pyuria; gastrointestinal infections produce diarrhea, which may be watery or bloody depending on the pathogen; skin and soft tissue infections cause erythema, warmth, and fluctuance if abscess is present; central nervous system infections produce headache, photophobia, nuchal rigidity, and altered mental status.

<image>Panel A: Fever mechanism pathway showing the sequence from bacterial infection releasing LPS and other PAMPs, to macrophage activation and release of endogenous pyrogens (IL-1, IL-6, TNF-alpha), to cytokines reaching the hypothalamus and inducing COX-2, to PGE2 production raising the thermoregulatory set point, to physiological responses (shivering, vasoconstriction) generating heat to reach the new set point, with temperature scale showing normal and elevated set points. Panel B: Cardinal signs of inflammation illustrated around a localized infection: cross-section of tissue showing dilated blood vessels causing redness (rubor) and heat (calor), leaky capillaries with plasma extravasation causing swelling (tumor), nerve endings being stimulated by mediators causing pain (dolor), and overall tissue dysfunction causing loss of function (functio laesa), with inflammatory mediators (prostaglandins, bradykinin, histamine) labeled. Panel C: Laboratory findings in bacterial infection displayed as a diagnostic panel: blood smear showing neutrophilia with band forms (left shift), elevated CRP and ESR bars on a graph, elevated procalcitonin indicating bacterial versus viral infection, and elevated lactate indicating tissue hypoperfusion, with interpretive notes for each finding. Panel D: Organ-specific manifestations montage showing respiratory infection (chest X-ray with consolidation, patient with productive cough), urinary infection (urinalysis with pyuria and bacteriuria), GI infection (patient with diarrhea, stool sample), skin and soft tissue infection (cellulitis with erythema and warmth, or abscess with fluctuance), and CNS infection (patient with nuchal rigidity, CSF tube showing turbidity), each with key clinical and laboratory features.</image>

Summary

• Pathogenesis follows sequential stages: exposure, adhesion, invasion, colonization, tissue damage, and spread; portal of entry and infectious dose influence clinical presentation
• Adhesins including pili and surface proteins mediate specific attachment to host cell receptors, determining tissue tropism; biofilms provide antibiotic-resistant bacterial communities on surfaces and implants
• Invasion mechanisms include trigger entry (type III secretion with cytoskeletal rearrangement) and zipper entry (tight receptor-ligand binding); intracellular survival requires evasion of phagolysosomal killing
• A-B toxins feature binding (B) and active (A) subunits; examples include diphtheria toxin (ADP-ribosylates EF-2), cholera toxin (ADP-ribosylates Gs elevating cAMP), and clostridial neurotoxins (cleave SNARE proteins)
• Superantigens cross-link MHC class II to TCR, causing massive non-specific T cell activation and cytokine storm manifesting as toxic shock syndrome
• Endotoxin (LPS Lipid A) activates TLR4 signaling, producing cytokines that cause fever, vasodilation, DIC, and organ dysfunction progressing to septic shock
• Immune evasion strategies include capsule (antiphagocytic), complement inhibition, antigenic variation, and intracellular survival
• Host defenses include innate immunity (barriers, phagocytes, complement, PRRs) and adaptive immunity (antibodies, T cells); immunopathology can result from excessive or misdirected responses
• Infections are classified as local versus systemic, acute versus chronic, primary versus opportunistic, and community versus healthcare-associated

Key Terms

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