Immune Defense by Pathogen Class & Microbial Immune Evasion
Which immune arm beats which microbe, and how microbes fight back
Matching defense to pathogen
The organizing principle. Where a microbe lives decides which arm of immunity can reach it. Organisms in blood, tissue fluid or on mucosal surfaces are exposed to antibody, complement and phagocytes. Organisms hiding in macrophage vesicles are killed only after T cells activate the macrophage. Organisms replicating in the cytosol, above all viruses, are eliminated by killing the infected cell. Parasites too large to engulf need a dedicated IgE–eosinophil response. Knowing these pairings lets you predict which infections follow a given immune defect.
| Pathogen class | Examples | Dominant defense | Failure → infection |
|---|---|---|---|
| Extracellular bacteria | S. pneumoniae, S. aureus, Neisseria, H. influenzae | Antibody, complement, neutrophils; Th17 (IL-17) | Antibody, complement or neutrophil defects; asplenia → encapsulated organisms |
| Intracellular (vesicular) | Mycobacteria, Salmonella, Histoplasma, Leishmania, Listeria | Th1 → IFN-γ → activated macrophages; granuloma | IL-12/IFN-γ receptor defects, anti-TNF therapy, advanced HIV |
| Viruses | HSV, VZV, CMV, influenza | Type I IFN, NK cells, CD8 CTLs; neutralizing antibody | NK- or T-cell deficiency → severe herpesvirus infection |
| Fungi | Candida, Aspergillus | Th17 at skin and mucosa; neutrophils against invasion | STAT3 or AIRE defects → mucocutaneous candidiasis; neutropenia → invasive disease |
| Helminths | Ascaris, Strongyloides, schistosomes | Th2 → IgE, eosinophils, mast cells (IL-4, IL-5, IL-13) | Glucocorticoids → Strongyloides hyperinfection |
Extracellular bacteria and mucosal fungi
Antibody. IgG opsonizes bacteria so phagocytes can seize them through Fc receptors, while IgG and secretory IgA neutralize toxins and block adhesion to epithelium. Toxoid vaccines (tetanus, diphtheria) protect purely by inducing neutralizing antibody against the toxin, not against the organism.
Complement. C3b opsonizes, C5a draws neutrophils to the site, and the C5b–C9 membrane attack complex lyses thin-walled gram-negative bacteria, which is why terminal complement deficiency predisposes to Neisseria.
Th17 cells. TGF-β plus IL-6 induce Th17 differentiation and IL-23 sustains it. IL-17 makes epithelium and fibroblasts release CXCL8 (IL-8) and G-CSF, recruiting and producing neutrophils; IL-22 induces β-defensins and other antimicrobial peptides. This arm guards skin and mucosa against S. aureus and fungi.
Mucocutaneous vs invasive Candida. Chronic mucocutaneous candidiasis (CMC) signals Th17 failure. In autosomal dominant hyper-IgE (Job) syndrome, STAT3 loss blocks Th17 differentiation, producing CMC with cold staphylococcal abscesses, eczema, retained primary teeth and very high IgE. In AIRE deficiency (APS-1), neutralizing autoantibodies against IL-17 and IL-22 cause CMC. Invasive candidemia instead reflects neutropenia, central lines or breached barriers.
Intracellular pathogens: the IL-12/IFN-γ loop
- Macrophage ingests the microbepresents antigen on MHC II and secretes IL-12
- IL-12 drives Th1 cells and NK cellsboth release IFN-γ
- IFN-γ activates the macrophageiNOS, reactive oxygen species and phagolysosome fusion kill mycobacteria, Salmonella, Histoplasma, Leishmania and Listeria
- Persistent antigen forms a granulomaepithelioid macrophages and giant cells ringed by lymphocytes, held together by TNF-α
Mendelian susceptibility to mycobacterial disease. Defects in IL-12 p40, IL-12Rβ1 (the most common), IFN-γ receptor 1 or 2, or STAT1 break the loop. Children develop disseminated BCG after vaccination, nontuberculous mycobacterial infection and recurrent nontyphoidal Salmonella, yet antibody levels and the neutrophil oxidative burst (dihydrorhodamine test) are normal, which separates this group from chronic granulomatous disease. Recombinant IFN-γ helps when the defect lies upstream (IL-12 or its receptor) but not in complete IFN-γ receptor deficiency.
Anti-TNF drugs (infliximab, adalimumab, etanercept) break down granulomas and reactivate latent TB and histoplasmosis; screen with an IGRA or PPD before starting.
Viruses and helminths
Type I interferons. Infected cells, and plasmacytoid dendritic cells in particular, sense viral nucleic acids and release IFN-α and IFN-β. Signaling through JAK1/TYK2 and STATs puts neighboring cells into an antiviral state: PKR phosphorylates eIF2α and halts translation, and 2′,5′-oligoadenylate synthetase activates RNase L to degrade RNA. Type I IFN also raises MHC I expression and activates NK cells.
NK cells, then CTLs. NK cells, stimulated by IFN-α/β and IL-12, kill infected cells within days, before adaptive immunity is ready. Virus-specific CD8 CTLs expand by about day 7–10 and kill cells displaying viral peptide on MHC I with perforin and granzymes (caspase-driven apoptosis) or Fas ligand. Neutralizing antibody follows, clearing free virions and preventing reinfection. Patients lacking NK cells suffer severe, recurrent herpesvirus infections (VZV, CMV, HSV).
Helminths. Worms too large to phagocytose trigger Th2 cells: IL-4 drives IgE class switching, IL-5 drives eosinophil production and activation, and IL-13 increases mucus and gut smooth-muscle contraction to expel worms. Antibody-coated larvae are attacked by eosinophils that release major basic protein (antibody-dependent cellular cytotoxicity), with IgE-armed mast cells amplifying the response. Eosinophilia with a tissue-invasive helminth is the classic laboratory clue.
How microbes evade immunity
| Strategy | Mechanism | Examples |
|---|---|---|
| Antigenic variation | Surface antigens change faster than antibody can follow | Gonococcal pilin (and Opa phase variation), trypanosome VSG, Borrelia recurrentis outer-membrane proteins, influenza drift and shift, HIV env |
| Capsule and sialic acid | Block C3b deposition and phagocytosis; sialic acid on capsule or LOS recruits factor H to inactivate C3b | S. pneumoniae, Hib, N. meningitidis, Klebsiella, E. coli K1, group B strep |
| Antibody sabotage | Protein A binds IgG Fc; IgA protease cleaves IgA1 at the hinge | S. aureus; S. pneumoniae, H. influenzae, Neisseria |
| Complement and chemotaxis sabotage | M protein binds factor H and fibrinogen; C5a peptidase destroys C5a | Group A strep |
| MHC I down-regulation | Viral proteins degrade or trap MHC I or starve it of peptide | CMV US2/US11, HSV ICP47 (blocks TAP), adenovirus E3-19K, HIV Nef |
| Survival in phagocytes | Block phagolysosome fusion or escape to the cytosol | M. tuberculosis (sulfatides, lipoarabinomannan), Legionella; Listeria (listeriolysin O) |
| Latency | Few antigens expressed; reactivation when T-cell immunity wanes | HSV and VZV in sensory ganglia, EBV in B cells |
Antigenic variation in practice. Gonorrhea reinfection is common and no vaccine exists because pilin genes keep recombining. African trypanosomes express one VSG at a time and switch, so parasitemia comes in waves; Borrelia recurrentis does the same with its outer-membrane proteins, and each relapse of fever is a new variant escaping the antibody that cleared the last. Influenza drift is point mutation in hemagglutinin or neuraminidase (seasonal epidemics); shift is reassortment of its segmented genome (pandemics).
The NK backstop. Lowering MHC I hides infected cells from CD8 CTLs but removes the signal that engages inhibitory KIRs on NK cells, so NK cells kill by missing self.
Encapsulated organisms and the spleen. Because capsules defeat complement opsonization, clearance depends on anticapsular IgG plus splenic macrophages and marginal-zone B cells; asplenic patients need pneumococcal, Hib and meningococcal vaccines.
Listeria spreads from cell to cell on ActA-driven actin tails and is barely touched by antibody, so its clearance depends on CD8 T cells and IFN-γ-activated macrophages. GAS M protein also cross-reacts with cardiac myosin, the molecular mimicry behind rheumatic fever.