Innate Antiviral Immunity — Questions

Each of these macrophage-produced cytokines has a characteristic systemic effect on the host.

Interleukin-1 (IL-1). Pyrogenic. Acts on the anterior hypothalamus to raise the thermoregulatory set-point, causing fever. It also drives the hepatic acute phase response (production of C- reactive protein, fibrinogen, and serum amyloid A). IL-1β is cleaved from its inactive precursor by caspase-1 within the inflammasome.

Tumour necrosis factor alpha (TNF-α). The classical cytokine of chronic catabolic illness. In sustained infection or malignancy, elevated TNF-α causes the cluster of muscle wasting, fat loss, and anorexia known as cachexia (originally called “cachectin”). In acute infection it also activates vascular endothelium and induces fever.

Interleukin-3 (IL-3). A haematopoietic growth factor. Together with granulocyte colony-stimulating factor (G-CSF), it drives neutrophil production in the bone marrow during acute infection, explaining the neutrophilia seen in many systemic infections.

The correct option pairs each cytokine with its principal systemic effect. The distractors swap real cytokines onto wrong endpoints.

Dendritic cells (DCs) are the dominant antigen-presenting cells and the critical bridge between innate and adaptive immunity. They are found in two functional states.

Immature DCs are highly endocytic, with low surface MHC class II, low costimulatory molecule expression (CD80 / CD86), and limited T-cell priming capacity. They are positioned as sentinels at portals of viral entry (Langerhans cells in the skin, lung-resident DCs in the airway, intestinal DCs in the gut).

Maturation is triggered when the DC senses viral PAMPs through its pattern-recognition receptors (TLRs, RIG-I, MDA5, cGAS–STING), or when it receives cytokine signals (type I IFN, TNF-α) from the inflamed microenvironment. On maturation the DC:

• Downregulates endocytic activity (it has captured what it needs).
• Upregulates MHC class I and MHC class II loaded with processed viral peptides.
• Upregulates the costimulatory molecules CD80 (B7-1) and CD86 (B7-2) needed for naïve T-cell activation.
• Upregulates the chemokine receptor CCR7, which directs migration along CCL19 / CCL21 gradients toward T cell zones of draining lymph nodes.

Cross-presentation is the special capacity of certain dendritic cells (cDC1) to load externally acquired viral antigen onto MHC class I, allowing CD8+ cytotoxic T cell priming against viruses that do not infect dendritic cells directly.

The correct option captures this sequence. The distractors describe biology that does not occur: DCs mature in tissue (not the bone marrow), maturation requires PRR signalling, mature DCs are poorly phagocytic, and DCs can present antigen taken up from the environment without themselves being infected.

The three nucleic-acid-sensing Toll-like receptors sit on the endosomal membrane, so that they detect viral nucleic acids only after the virus has been internalised by the cell.

• TLR3: double-stranded RNA.
• TLR7 and TLR8: single-stranded RNA.
• TLR9: unmethylated CpG DNA.

The wider family and its ligands:

TLR	Location	Principal ligand
TLR1 / TLR2 / TLR6 / TLR10	Cell surface	Microbial cell-wall lipoproteins and peptidoglycans
TLR3	Endosome	Double-stranded RNA
TLR4	Cell surface	Bacterial lipopolysaccharide (LPS)
TLR5	Cell surface	Bacterial flagellin
TLR7 / TLR8	Endosome	Single-stranded RNA
TLR9	Endosome	Unmethylated CpG DNA
TLR11 / TLR12 / TLR13	Endosome	Toxoplasma gondii (11, 12); bacterial ribosomal RNA (13)

The defences fall into four layers: barriers, recognition machinery, soluble and cellular effectors, and cell-death programmes.

Barriers. Intact skin and the mucosal epithelium of the respiratory, gastrointestinal, and urogenital tracts block viral entry. Mucociliary clearance, gastric acid, bile, lysozyme, and pulmonary surfactant reduce the inoculum reaching the underlying immune system, all before any immune cell is involved.

Recognition. Infected and sentinel cells detect pathogen-associated molecular patterns (PAMPs) through germline-encoded pattern-recognition receptors (PRRs), in four families: Toll-like receptors (TLRs) on the surface (TLR2, TLR4) and in endosomes (TLR3 for double-stranded RNA, TLR7 / TLR8 for single-stranded RNA, TLR9 for unmethylated CpG DNA); cytoplasmic RIG-I-like receptors (RIG-I for short 5’-triphosphate dsRNA, MDA5 for long dsRNA); the cytoplasmic cGAS–STING pathway, detecting viral DNA; and NOD-like receptors (NLRs) assembling inflammasomes (NLRP3, AIM2). Engagement converges on IRF3, IRF7, and NF-κB, driving interferon and inflammatory cytokine production.

Soluble effectors. Type I interferons (IFN-α, IFN-β) act through IFNAR to switch on hundreds of interferon-stimulated genes (ISGs) via JAK–STAT, blocking replication at multiple steps: protein kinase R (PKR) shuts down translation, 2’–5’ OAS / RNase L degrades viral RNA, Mx GTPases block nuclear import, IFITM proteins block fusion. Type III (IFN-λ) acts on epithelium; type II (IFN-γ), from T and natural killer (NK) cells, activates macrophages and amplifies the type I response. Restriction factors, constitutively expressed and interferon-boosted, add to this: TRIM5α blocks early HIV-1 uncoating, APOBEC3G hypermutates retroviral cDNA, tetherin (BST-2) holds budding virions on the surface, and SAMHD1 depletes the dNTP pool needed for reverse transcription.

Cellular effectors. Phagocytes (macrophages, dendritic cells, neutrophils) engulf virions and debris; dendritic cells carry viral antigen to draining lymph nodes and prime the adaptive response, the critical innate-adaptive link. NK cells lyse infected cells by perforin and granzyme, recognising them through missing-self (loss of MHC class I) and stress-induced ligands (MICA, MICB).

Cell death. Apoptosis (caspase-mediated, silent), necroptosis (RIPK1 / RIPK3 / MLKL), and pyroptosis (inflammasome, caspase-1, gasdermin D pores, IL-1β release) all remove infected cells, pyroptosis additionally recruiting further immune cells. Every layer is triggered by viral PAMPs through PRRs or by cellular stress signals (DAMPs); the integration of these signals over the first hours determines whether infection is contained and programmes the adaptive response.

NK cells recognise infected cells through three mechanisms.

Missing-self. Healthy cells display MHC class I, which engages NK inhibitory receptors (killer-cell immunoglobulin-like receptors, KIRs; and CD94 / NKG2A) and switches off cytotoxicity, so normal cells are spared. Many viruses, notably herpesviruses, downregulate MHC class I to escape CD8+ cytotoxic T cells; this loss removes the inhibitory signal and the cell is killed. The hypothesis was proposed by Klas Kärre in 1986.

Stress-induced ligands. Infected cells upregulate MICA, MICB, and the ULBP proteins, recognised by the activating receptor NKG2D; the natural cytotoxicity receptors NKp30, NKp44, and NKp46 are further activating receptors. Their engagement tips the balance towards killing even if some MHC class I remains.

Antibody-dependent cellular cytotoxicity (ADCC). CD16 (FcγRIII) binds IgG bound to viral antigens on the infected surface, triggering perforin and granzyme release independently of MHC class I and linking NK killing to the humoral response once virus-specific IgG is available.

The killing decision is the balance of activating and inhibitory signals: in a normal cell inhibition dominates; in an infected cell MHC class I loss reduces inhibition while stress ligands raise activation, and the NK cell kills through perforin and granzyme.

The cGAS–STING pathway is the principal cytosolic DNA-sensing pathway in mammalian cells.

The mechanism in three steps:

1. Detection. Cyclic GMP-AMP synthase (cGAS) is a cytosolic enzyme that binds double-stranded DNA in a sequence-independent manner. Any DNA in the cytoplasm activates it: viral DNA from herpesviruses or DNA viruses, retroviral cDNA intermediates from HIV, mitochondrial DNA that has leaked out, or fragments of damaged self-DNA.
2. Second messenger. Activated cGAS catalyses the synthesis of the cyclic dinucleotide 2’3’-cGAMP (cyclic guanosine monophosphate–adenosine monophosphate) from ATP and GTP.
3. STING activation. cGAMP binds the stimulator of interferon genes (STING), a transmembrane protein anchored in the endoplasmic reticulum. STING traffics from the ER to the Golgi, recruits and activates the kinase TBK1, which phosphorylates IRF3. Activated IRF3 translocates to the nucleus and drives transcription of type I and type III interferons.

The cGAS–STING axis is also responsible for the type I interferon response to retroviral reverse-transcription intermediates (an important innate barrier to HIV) and is a major contributor to the interferonopathies seen in conditions such as Aicardi–Goutières syndrome, where impaired clearance of self-derived cytosolic nucleic acids leads to chronic activation of the pathway.

The other options describe correct molecules in the wrong roles: RIG-I and MDA5 sense cytosolic RNA (not DNA); TLR9 senses unmethylated CpG DNA in endosomes (not the cytoplasm); and the NLRP3 inflammasome triggers pyroptosis rather than the IRF3-driven interferon response.

The behaviour of an NK cell is governed by the balance between activating receptors (such as NKG2D, which recognises stress-induced ligands MICA and MICB) and inhibitory receptors (such as the killer-cell immunoglobulin-like receptors, KIRs, and CD94 / NKG2A, which all recognise MHC class I).

In a healthy cell, MHC class I is constitutively displayed and engages the inhibitory receptors, switching off NK cytotoxicity. Many viruses, especially the herpesviruses, downregulate MHC class I to escape recognition by CD8+ cytotoxic T cells. This is, however, a double-edged strategy: the loss of MHC class I removes the inhibitory signal to NK cells, and the cell becomes a target for missing-self killing. The hypothesis was formalised by Klas Kärre in 1986.

This is why some herpesviruses (most notably human cytomegalovirus) have evolved a second layer of evasion: HCMV’s UL18 protein is a class I MHC homologue that engages the NK inhibitory receptor LIR-1 with high affinity, restoring the inhibitory signal without making the cell visible to cytotoxic T cells.

The other options describe mechanisms that do not occur in this scenario: NK cells do not require MHC class II, do not require antibody for direct missing-self killing, and are not inhibited by interferon (interferon enhances NK activity).

The clinical pattern here, a previously healthy child who develops herpes simplex encephalitis (HSE) after primary HSV-1 infection while controlling other infections normally, points to a specific inborn error of immunity.

The biology. TLR3 sits on the endosomal membrane of cortical neurons, oligodendrocytes, and astrocytes in the central nervous system. It binds double-stranded RNA, which is generated during HSV-1 replication, and signals through the adaptor TRIF to activate IRF3 and produce type I and type III interferons. This localised interferon response is essential for restricting HSV-1 spread in the central nervous system.

The genetic syndrome. Autosomal-recessive or autosomal-dominant loss-of-function mutations in TLR3, or in its downstream signalling proteins UNC93B1 and TRIF, predispose specifically to herpes simplex encephalitis in children with primary HSV-1 infection. Patients control HSV at peripheral sites (skin, mucosa) normally, because peripheral defence relies on other pattern-recognition pathways, particularly the cytosolic cGAS–STING pathway and IFN-α / β from plasmacytoid dendritic cells.

Implication for the wider immunology of antiviral defence. This syndrome demonstrates two general principles. First, pattern- recognition receptor pathways are not redundant: a single sensor can be essential for control of a specific virus at a specific anatomical site. Second, the innate response is compartmentalised by tissue: the CNS relies more heavily on TLR3-mediated type III interferon than the periphery, which is why a partial defect in this pathway manifests as an organ-specific phenotype rather than a systemic immunodeficiency.

Similar tissue- and virus-specific susceptibilities have been identified for STAT1 mutations (mycobacterial and viral disease), IFNAR1 / IFNAR2 deficiency (severe disease from live-attenuated viral vaccines), and the more recently described autoantibodies against type I interferons in severe COVID-19.

Natural killer (NK) cells are governed by the balance between activating receptors (which detect stress-induced ligands such as MICA / MICB) and inhibitory receptors (which detect MHC class I on healthy cells). When a virus downregulates the host’s own MHC class I to escape CD8+ cytotoxic T cell recognition, the cell loses its inhibitory signal to NK cells and is killed by the missing-self mechanism. Several viruses circumvent this by encoding their own MHC class I homologues, which engage NK inhibitory receptors and restore the inhibitory signal without making the cell visible to cytotoxic T cells.

Viral mechanisms of NK evasion:

Mechanism	Examples	Outcome
(1) Homologues of class I MHC	Herpesviruses (e.g., HCMV UL18)	Bind to NK cell inhibitory receptor; inhibit NK cytotoxicity
(2) Regulation of class I MHC expression on the target cell	Herpesviruses, simian immunodeficiency virus (SIV)	Inhibition of NK cytotoxicity
(3) Virus-coded protein interfering with NK activating-receptor / ligand interactions	Herpesviruses, HIV, human T-lymphotropic virus (HTLV)	Inhibition of NK cytotoxicity and IFN-γ production
(4) Inhibition of NK-activating cytokine by binding the cytokine or producing a chemokine antagonist	Herpesviruses, papillomaviruses	Inhibition of IFN-γ production and trafficking
(5) Direct effects of virions (block an inhibitory receptor or directly infect NK cells)	Herpesviruses, HIV; hepatitis C virus E2 binds CD81 on NK cells	Reduces NK cell activity

A well-characterised example is the HCMV protein UL18, a class I MHC homologue that binds the NK inhibitory receptor LIR-1 with very high affinity, suppressing NK cytotoxicity even when the virus has simultaneously downregulated genuine cellular MHC class I to escape CD8+ T cells. This dual strategy is why human cytomegalovirus is particularly dangerous in patients with profound T cell deficiency (transplant recipients, advanced HIV) and in congenital infection.

Restriction factors are host proteins continuously expressed in many cell types and further upregulated by interferon. Each blocks a specific step of viral replication. The presence of a virus-encoded counter-evasion protein for each restriction factor is strong evidence of their functional importance.

Restriction factor	Mechanism	Virus targeted
TRIM5α	Binds the incoming retroviral capsid and triggers premature uncoating and proteasomal degradation	HIV-1 (particularly the rhesus monkey TRIM5α; the human version is less effective against HIV-1, which is one reason HIV-1 successfully replicates in humans)
APOBEC3G	A cytidine deaminase that introduces G-to-A hypermutation into nascent retroviral DNA during reverse transcription	HIV-1; counter-evasion by HIV Vif, which marks APOBEC3G for proteasomal degradation
Tetherin (BST-2)	A surface protein anchored at both ends of an enveloped virion’s lipid bilayer; physically holds budding virions on the cell membrane	HIV-1 and other enveloped viruses; counter-evasion by HIV Vpu, which degrades tetherin
SAMHD1	A dGTP-dependent triphosphohydrolase that depletes the cellular dNTP pool, starving reverse transcription	HIV-1 in myeloid cells and resting T cells; counter-evasion by HIV-2 / SIV Vpx, which targets SAMHD1 for degradation
IFITM proteins (1, 2, 3)	Embed in endosomal membranes and block fusion of enveloped viruses	Influenza, dengue, Zika, SARS-CoV-2
Mx GTPases (MxA, MxB)	Form oligomeric structures that trap viral nucleocapsids and block nuclear entry	Influenza, hantaviruses; MxB additionally blocks HIV-1

The correct pairing is tetherin (BST-2), which holds budding virions on the cell surface. The distractors swap real mechanisms to wrong factors: APOBEC3G is the cytidine deaminase, TRIM5α targets capsid uncoating, SAMHD1 depletes the dNTP pool, and IFITM3 blocks membrane fusion.

The inflammasome is a cytosolic multiprotein complex that acts as a threshold sensor for intracellular danger. It consists of a sensor protein (such as NLRP3 or AIM2), the adaptor ASC, and pro-caspase-1.

Triggering:

• NLRP3 responds to a broad set of stress signals: viral replication intermediates, mitochondrial dysfunction, reactive oxygen species, potassium efflux, and lysosomal rupture.
• AIM2 binds cytosolic double-stranded DNA directly.

On activation the sensor oligomerises, recruits ASC through pyrin domain interactions, and ASC in turn recruits pro-caspase-1. Pro-caspase-1 self-cleaves into active caspase-1, which then cleaves two key substrates:

1. Pro-IL-1β and pro-IL-18 are cleaved into the mature pro-inflammatory cytokines IL-1β and IL-18, which are then released into the extracellular space.
2. Gasdermin D (GSDMD) is cleaved, and its N-terminal fragment oligomerises and inserts into the plasma membrane, forming pores. The cell lyses, releasing its contents and amplifying inflammation.

This lytic, inflammatory form of cell death is pyroptosis, the loud counterpart to apoptotic silent removal. Pyroptosis is a major driver of the severe inflammatory phenotype of influenza, hantavirus pulmonary syndrome, and severe COVID-19. Several viruses encode inflammasome inhibitors to dampen the response (e.g. Kaposi sarcoma herpesvirus ORF63).

Inflammasome activation is distinct from the apoptosis (caspases 3, 6, 7) and necroptosis (RIPK1 / RIPK3 / MLKL) pathways, and it is independent of cytotoxic T cell engagement.

Type III interferons comprise IFN-λ1 (also called IL-29), IFN-λ2 (IL-28A), IFN-λ3 (IL-28B), and IFN-λ4, all encoded on human chromosome 19. They bind the receptor complex IFNLR1 + IL-10R2, which is expressed predominantly on epithelial cells of the respiratory and gastrointestinal tracts, on hepatocytes, and on melanocytes. This receptor distribution restricts IFN-λ action to the mucosal and hepatic compartments where it acts as a tissue- specific antiviral defence, with less of the systemic inflammation that accompanies type I interferon signalling on most cell types.

Downstream signalling uses the same JAK and STAT components as type I interferons, leading to the same antiviral interferon-stimulated genes, but the restricted receptor distribution and the somewhat prolonged induction profile of IFN-λ produce a different functional niche.

Clinical relevance. A single-nucleotide polymorphism in the IFN-λ3 / IFN-λ4 region is the strongest known host genetic predictor of:

• Spontaneous clearance of acute hepatitis C virus infection.
• Treatment response to the older interferon-based hepatitis C regimens (the CC genotype at rs12979860 predicts a much higher sustained virological response rate than the CT or TT genotypes).

IFN-λ has also attracted attention as a potential therapeutic for respiratory viral infections (including SARS-CoV-2), since it can restrict viral replication at the mucosal portal of entry without the systemic cytokine effects of type I interferon.

Natural killer (NK) cells are large granular lymphocytes that lyse infected cells without prior sensitisation or antigen specificity. Innate but sharing a lineage with T cells, they act within the first one to two days, and are identified by CD56 (neural cell adhesion molecule, NCAM) and CD16 (the low-affinity IgG receptor, FcγRIII).

Their activity is set by two opposing sets of receptors. Activating receptors (the natural cytotoxicity receptors NKp30, NKp44, NKp46, and NKG2D) recognise stress-induced ligands such as MICA and MICB on infected or transformed cells. Inhibitory receptors (killer-cell immunoglobulin-like receptors, KIRs; and CD94 / NKG2A) recognise major histocompatibility complex (MHC) class I on healthy cells and switch off cytotoxicity.

With normal MHC class I, inhibition dominates and no killing occurs. Viruses commonly downregulate MHC class I to escape CD8+ cytotoxic T cells; this removes the inhibitory signal, activation dominates, and the NK cell kills, the missing-self hypothesis of Klas Kärre.

Killing uses preformed granules of perforin (forming pores in the target membrane) and granzymes (serine proteases that enter and trigger caspase-mediated apoptosis), unlike CD8+ T cells, which need activation and clonal expansion first. Activated NK cells also secrete IFN-γ, TNF-α, IL-4, and IL-13, which activate macrophages, recruit leukocytes, and shape the adaptive response, so NK cells clear virus both directly by cytolysis and indirectly through cytokine-mediated priming.

The first line of defence is the host’s outer surfaces, blocking virus before any immune cell is involved, grouped as physical and chemical.

Physical barriers. Intact keratinised, multilayered skin is impermeable to almost all viruses unless broken (injection, trauma, surgery, sexual contact, arthropod bite). The mucosal epithelium of the respiratory, gastrointestinal, and urogenital tracts is sealed by tight junctions. Mucociliary clearance traps inhaled particles in a mucus blanket and sweeps them out by ciliary beating. Eyelashes, eyebrows, and other hairs filter ocular and respiratory surfaces, and tears, saliva, urine, and intestinal peristalsis flush virions mechanically.

Chemical barriers. Low-pH gastric acid inactivates most ingested viruses except acid-resistant agents (enteroviruses, hepatitis A virus, rotavirus, norovirus). Bile salts act as detergents on enveloped viruses, one reason most enteric viruses are non-enveloped. Lysozyme in saliva, tears, and nasal secretions cleaves bacterial peptidoglycan and has direct activity against some enveloped viruses. Lactoferrin in milk, tears, and secretions sequesters iron and is directly antiviral. Surfactant proteins in the alveolar lining bind and neutralise viral glycoproteins.

These barriers are not absolute, but they reduce the inoculum reaching the immune system and shape which viruses establish infection through each route.

Interferons (IFNs) are cytokines released by virus-infected cells that signal to neighbouring cells and to the wider immune system. Alick Isaacs and Jean Lindenmann first described them in 1957, showing that influenza-infected cells released a non-viral protein that protected fresh cells from the same or an unrelated virus. They are classified into three types by the receptor they bind.

	Type I	Type II	Type III
Examples	IFN-α (many species-specific subtypes); IFN-β; IFN-ε, IFN-κ, IFN-ω	IFN-γ	IFN-λ1, IFN-λ2, IFN-λ3, IFN-λ4
Produced by	Most nucleated cell types	T cells and natural killer (NK) cells	Many cell types, but action restricted by receptor distribution
Receptor	IFNAR (heterodimer of IFNAR-1 and IFNAR-2)	IFNGR (tetramer of two IFNGR-1 / IFNGR-2 heterodimers)	IFNLR1, expressed mainly on epithelial cells, hepatocytes, and melanocytes
Signalling and effect	JAK / TYK2 / STAT cascade. Forms the ISGF3 complex (STAT1, STAT2, IRF9) which binds interferon-stimulated response elements (ISREs) and induces hundreds of interferon-stimulated genes (ISGs)	JAK1 / JAK2 / STAT1. Binds γ-activated sites (GAS). Activates macrophages, recruits leukocytes, potentiates Type I IFN effects	JAK / STAT cascade. Induces ISGs but is restricted to epithelial surfaces

Type I (IFN-α, IFN-β). The principal direct antiviral interferons, produced by almost any cell detecting intracellular infection. Secreted IFN binds IFNAR on neighbouring cells, triggering JAK–STAT signalling and ISG expression that places the cell in an antiviral state (the bystander effect). IFN-α is used in chronic hepatitis B and C, IFN-β in relapsing multiple sclerosis.

Type II (IFN-γ). Not directly induced by viral infection; produced by activated T cells (especially Th1) and NK cells. It activates macrophages, recruits leukocytes, and amplifies type I effects, and is the major cytokine of cell-mediated immunity against intracellular pathogens.

Type III (IFN-λ). The most recently described family, encoded on chromosome 19, using a distinct receptor (IFNLR1) expressed mainly on epithelial cells of the respiratory and gastrointestinal tracts, on hepatocytes, and on melanocytes. It provides tissue-specific mucosal and hepatic defence with less systemic inflammation than type I. A single-nucleotide polymorphism near IFNL3, which influences hepatocyte receptor density, is the strongest predictor of spontaneous and treatment-induced hepatitis C clearance.

All three converge on ISG induction. Notable products: protein kinase R (PKR), shutting down host translation via eIF-2α; the 2’–5’ oligoadenylate synthetase (OAS) / RNase L system, degrading viral RNA; the Mx GTPases, blocking nuclear import; the IFITM proteins, blocking enveloped virus entry; and ISG15, a ubiquitin-like modifier with broad antiviral activity.

Three forms of programmed cell death that remove virus-infected cells but differ in machinery, inflammatory output, and which viruses inhibit each.

Apoptosis. Caspase-mediated and immunologically silent: the cell shrinks, chromatin condenses, the membrane stays intact, and the cell is phagocytosed before its contents leak. Two pathways converge on the effector caspases (3, 6, 7): the intrinsic (mitochondrial) pathway, where stress drives BAX / BAK pores, cytochrome c release, and assembly of the APAF-1 / pro-caspase-9 apoptosome; and the extrinsic (death receptor) pathway, where Fas, TNF receptor 1, and TRAIL receptors assemble the DISC to activate caspase-8. Many viruses block it (HSV ICP6 and CMV vICA inhibit caspase-8) to preserve their replication factory.

Necroptosis. A lytic, inflammatory backup triggered when caspase-8 is blocked, usually by a viral inhibitor: RIPK1 and RIPK3 form the necrosome, which phosphorylates MLKL; MLKL oligomerises into membrane pores, lysing the cell and releasing DAMPs that recruit immune cells. The sensor ZBP1 triggers it in influenza-infected cells.

Pyroptosis. Inflammasome-driven and highly inflammatory: NLRP3 (stress signals) and AIM2 (cytosolic DNA) recruit ASC and activate caspase-1, which cleaves pro-IL-1β and pro-IL-18 to their mature secreted forms and cleaves gasdermin D, whose N-terminal fragment forms membrane pores that lyse the cell and release the cytokines. It is implicated in severe influenza, hantavirus pulmonary syndrome, and severe COVID-19.

Apoptosis is silent removal, necroptosis the lytic backup when apoptosis is blocked, pyroptosis inflammatory inflammasome-linked death; the balance shapes both clearance and disease severity.

The innate system cannot recognise the unique antigens of any particular virus. Instead it detects conserved molecular signatures shared across whole classes of pathogens, using germline-encoded sensors.

Pathogen-associated molecular patterns (PAMPs) are conserved microbial structures absent from the host. The major viral PAMPs are nucleic-acid structures either absent from healthy human cells or present in unusual compartments: double-stranded RNA (a replication intermediate of many RNA viruses), single-stranded RNA in endosomes, unmethylated CpG-rich DNA, and 5’-triphosphate RNA. Some envelope glycoproteins and capsid proteins also act as PAMPs.

Damage-associated molecular patterns (DAMPs) are endogenous molecules released by stressed or dying host cells: HMGB1 (a chromatin protein), ATP, uric acid, and heat-shock proteins. They signal tissue damage regardless of any pathogen. Many DAMPs engage the same receptors as PAMPs, which is why infection and sterile injury both trigger an innate response.

Pattern-recognition receptors (PRRs) are the host’s germline-encoded sensors for PAMPs and DAMPs, constitutively expressed in many cell types, in four main families relevant to viral infection.

PRR family	Location	Examples and viral ligands
Toll-like receptors (TLRs)	Cell surface and endosomes	TLR3 (endosomes, dsRNA); TLR7 / TLR8 (endosomes, ssRNA); TLR9 (endosomes, unmethylated CpG DNA); TLR2 and TLR4 (cell surface, some viral envelope proteins)
RIG-I-like receptors (RLRs)	Cytoplasm	RIG-I (retinoic acid-inducible gene I; detects short 5’-triphosphate dsRNA); MDA5 (melanoma differentiation-associated protein 5; detects long dsRNA)
Cytosolic DNA sensors	Cytoplasm	cGAS (cyclic GMP-AMP synthase) detects cytosolic DNA and produces cGAMP, a second messenger that activates STING (stimulator of interferon genes) on the endoplasmic reticulum
NOD-like receptors (NLRs) and C-type lectins	Cytoplasm; cell surface	NLRP3, AIM2 (inflammasome assembly); DC-SIGN, Mannose receptor (recognise envelope glycoproteins)

Recognition and signalling. PRR engagement triggers cascades converging on a small set of transcription factors: IRF3 and IRF7 (driving type I and type III interferons) and NF-κB (driving inflammatory cytokines such as IL-6, TNF-α, and IL-1β). TLR3 in a dendritic-cell endosome detects dsRNA, signals through the adaptor TRIF, activates the kinases TBK1 and IKKε, and phosphorylates IRF3 to induce type I interferon. Cytosolic RIG-I detects 5’-triphosphate dsRNA, signals through the mitochondrial adaptor MAVS, and produces the same IRF3 and NF-κB activation. The cGAS–STING pathway responds to cytosolic DNA from DNA viruses or leaked self-DNA and likewise converges on IRF3.

The combined output is rapid local interferon and cytokine production, recruitment of innate cells, and priming of the adaptive response. Genetic defects produce specific susceptibilities: people with TLR3 or downstream signalling mutations are unusually prone to herpes simplex encephalitis, showing how a single PRR pathway can be essential for controlling a specific virus at a specific anatomical site.

Interferon production is triggered when pattern-recognition receptors (PRRs) detect viral pathogen-associated molecular patterns (PAMPs), mostly viral nucleic acids in compartments where they would not normally appear.

The major stimuli and their sensors:

PAMP	Sensor	Location	Downstream adaptor
Double-stranded RNA	TLR3	Endosome	TRIF
Double-stranded RNA, short 5’-triphosphate	RIG-I	Cytoplasm	MAVS (on mitochondria)
Double-stranded RNA, long	MDA5	Cytoplasm	MAVS
Single-stranded RNA	TLR7, TLR8	Endosome	MyD88
Unmethylated CpG DNA	TLR9	Endosome	MyD88
Cytosolic DNA	cGAS, producing cGAMP	Cytoplasm	STING (on endoplasmic reticulum)

All these pathways converge on the interferon regulatory factors IRF3 and IRF7 (driving type I and type III interferons) and NF-κB (driving inflammatory cytokines such as TNF-α and IL-6).

Plasmacytoid dendritic cells (pDCs) are the dominant type I interferon producers, constitutively expressing high TLR7, TLR9, and IRF7, and can make up to 1,000 times more per cell than other cell types.

Positive feedback amplification. Secreted type I IFN binds IFNAR on neighbouring and producing cells and, through JAK–STAT, induces interferon-stimulated genes (ISGs) including IRF7 itself, massively amplifying local interferon production.

Damage-associated molecular patterns (DAMPs) from stressed or dying cells (HMGB1, ATP, uric acid) also contribute through the same PRRs.

When secreted type I interferon (IFN-α or IFN-β) binds IFNAR on a neighbouring cell, it places that cell in an antiviral state: resistant to productive infection, primed to self-destruct if infected, and signalling its presence to the wider immune system.

Signalling cascade. IFN-α / β binding to IFNAR1 / IFNAR2 activates the kinases JAK1 and TYK2, which phosphorylate STAT1 and STAT2; these heterodimerise with IRF9 to form the ISGF3 complex, which binds interferon-stimulated response elements (ISREs) and switches on hundreds of interferon-stimulated genes (ISGs).

Direct antiviral ISG products block replication at multiple steps: protein kinase R (PKR), activated by dsRNA, phosphorylates eIF-2α and shuts down all protein synthesis; 2’–5’ oligoadenylate synthetase (OAS), also dsRNA-activated, makes 2’–5’ oligomers that switch on RNase L to cleave cytoplasmic single-stranded RNA; Mx GTPases (MxA, MxB) trap viral nucleocapsids and block nuclear import (influenza, hantaviruses); IFITM proteins (IFITM1–3) block enveloped-virus fusion at late endosomes (influenza, dengue, Zika, SARS-CoV-2); ISG15 conjugates to proteins (ISGylation) with broad antiviral effect; and viperin / RSAD2 disrupts the lipid rafts some enveloped viruses bud from.

Restriction factors, constitutively expressed and interferon-boosted: TRIM5α binds incoming retroviral capsids and triggers premature uncoating; APOBEC3G hypermutates nascent retroviral DNA (G-to-A); tetherin (BST-2) holds budding virions on the membrane; SAMHD1 depletes the dNTP pool needed for reverse transcription.

Indirect effects. ISGs upregulate MHC class I, making infected cells more visible to CD8+ cytotoxic T cells; lower the threshold for apoptosis; activate NK cells in the microenvironment; and drive dendritic-cell maturation and T cell priming, making type I IFN a critical adjuvant for the adaptive response.

Type II IFN-γ signals through STAT1 homodimers binding gamma-activated sites (GAS), inducing an overlapping gene set centred on macrophage activation. Type III IFN-λ uses a similar JAK–STAT cascade but on epithelium and hepatocytes, giving localised mucosal defence without systemic inflammation.

Once a virus penetrates the anatomical barriers, the innate response is the host’s first active defence. It engages within minutes to hours, needs no prior exposure, and works through integrated mechanisms that restrict early infection and limit spread to neighbouring tissue.

Immediate recognition through germline-encoded pattern-recognition receptors (PRRs) detecting generic pathogen-associated molecular patterns (PAMPs) rather than antigen-specific structures.

Activation and recruitment of innate cells (macrophages, dendritic cells, natural killer cells, neutrophils) to the site, driven by cytokines and chemokines.

Direct antiviral action through the type I and type III interferon programme, switching on hundreds of interferon-stimulated genes (ISGs) in neighbouring cells and making them resistant before the virus arrives, the bystander effect.

Elimination of infected cells by NK cell lysis and by apoptosis, necroptosis, or pyroptosis, removing the factories the virus depends on.

Shaping the adaptive response. Dendritic cells carry viral antigen to draining lymph nodes to prime T and B cell responses, and the innate cytokine context biases helper T cells towards Th1 against most viruses.

The innate response is broadly specific rather than antigen-specific, short-lived, and lacks memory; the innate-adaptive line is blurred, because the same pathways that limit early replication also prime and direct the adaptive response that follows.

Several cell populations contribute, each with a distinct role and timescale.

Phagocytes. Macrophages are tissue-resident phagocytes named by location (Kupffer cells in liver, alveolar macrophages in lung, microglia in the central nervous system, Langerhans cells in skin, technically dendritic, and splenic macrophages); they engulf virions and debris, make inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-12), present antigen, and dominate by 24 hours. Dendritic cells (DCs) are the most efficient antigen-presenting cells: plasmacytoid DCs are the major source of type I interferon, conventional DCs carry antigen to draining lymph nodes to prime adaptive immunity, making DCs the critical innate-adaptive bridge. Neutrophils are short-lived granulocytes recruited by CXCL8 / IL-8, important against bacteria but with a more limited antiviral role.

Cytotoxic cells. Natural killer (NK) cells are large granular lymphocytes that lyse infected cells via missing-self (loss of MHC class I) and stress-induced ligands; they appear within one to two days and produce IFN-γ.

Sentinel cells. Mucosal epithelial cells express PRRs and produce interferons, defensins, and chemokines on infection. Innate lymphoid cells (ILCs) are tissue-resident lymphocytes lacking antigen-specific receptors but making the same cytokines as T helper subsets; NK cells are group 1 ILCs.

Soluble defences also support the response: complement, natural antibodies from B1 lymphocytes, and hepatic acute phase reactants.

A network of soluble signalling molecules coordinates the innate response: pro-inflammatory cytokines, recruiting chemokines, antimicrobial peptides, the interferon system, and complement.

Pro-inflammatory cytokines. TNF-α (from macrophages and NK cells) activates vascular endothelium for leukocyte recruitment, induces fever, and drives cachexia, acting through NF-κB. IL-1β is pyrogenic, drives the hepatic acute phase response, and activates lymphocytes; caspase-1 cleaves it from pro-IL-1β in the inflammasome. IL-6 drives acute phase reactants (C-reactive protein, fibrinogen, serum amyloid A) and B cell differentiation. IL-12 (from macrophages and dendritic cells) activates NK cells and polarises naïve CD4+ T cells towards Th1. IL-15 maintains NK and memory CD8+ T cell populations. IL-18, an inflammasome product, amplifies IFN-γ from NK and T cells.

Chemokines. CXCL8 / IL-8 recruits neutrophils; CXCL10 / IP-10 (IFN-γ-inducible) recruits activated T cells; CCL2 / MCP-1 recruits monocytes; CXCL12 / SDF-1 is constitutive and serves as a co-receptor for HIV-1 entry through CXCR4.

Antimicrobial peptides. Small cationic peptides that disrupt enveloped virus membranes, some with antibacterial activity: α-defensins (neutrophils, Paneth cells), β-defensins (skin and mucosal epithelium), and cathelicidins (LL-37).

Interferons. The central antiviral cytokines: type I IFN-α / β, type II IFN-γ, and type III IFN-λ.

Complement. A serum cascade (classical, alternative, lectin pathways) that opsonises virions, lyses enveloped virions via the membrane attack complex, and recruits neutrophils through anaphylatoxins (C3a, C5a).