Innate Antiviral Immunity

A virus invading the human host must first breach a series of natural barriers at the portal of entry. If it succeeds, it encounters the innate immune system, a defence that is continuously present, broadly specific rather than antigen-specific, and operates within minutes to hours. The innate response is the dominant arm of antiviral defence during the first days of infection, before the antigen-specific adaptive response has had time to assemble. It also shapes that adaptive response. The line between innate and adaptive is not as sharp as the textbook division suggests, because many of the cytokines and signalling pathways that limit early viral replication also prime and direct the adaptive response that follows.

Anatomical and chemical barriers

The intact skin and the mucosal epithelium of the respiratory, gastrointestinal, and urogenital tracts form a physical barrier against viral entry, supported by secretions and clearance mechanisms that block, wash away, or inactivate the great majority of incoming viruses at the portal of entry.

Physical barriers are structural surfaces.

• Intact skin. The multilayered, keratinised epidermis is impermeable to almost all viruses unless it is broken (by injection, trauma, surgery, sexual contact, or arthropod bite).
• Mucosal epithelium of the respiratory, gastrointestinal, and urogenital tracts, with tight junctions between epithelial cells.
• Mucociliary clearance in the respiratory tract: a mucus blanket traps inhaled viral particles, and the synchronised beating of ciliated columnar epithelium sweeps them up the airway.
• Mechanical flushing by tears, saliva, urine, and intestinal peristalsis.

Chemical barriers are the secretions that wash, neutralise, or inactivate virions on those surfaces.

• Gastric acid (hydrochloric acid in the stomach) inactivates most ingested viruses except acid-resistant agents such as enteroviruses, hepatitis A virus, rotavirus, and norovirus.
• Bile salts in the small intestine act as detergents and inactivate enveloped viruses, which is one reason most enteric viruses are non-enveloped.
• Lysozyme in saliva, tears, and nasal secretions.
• Lactoferrin in milk, tears, and other secretions sequesters iron and has direct antiviral activity.
• Surfactant proteins in the alveolar lining bind viral glycoproteins.

These barriers are not absolute, but they reduce the inoculum that reaches the underlying immune system and shape which viruses successfully establish infection through each anatomical route.

Innate versus adaptive immunity

Property	Innate immunity	Adaptive immunity
Speed of response	Minutes to hours	Days; response is accelerated when the same antigen is met on subsequent occasions
Antigen specificity	No	Yes
Duration	Days (prolonged if antigenic stimulus continues)	Weeks
Memory	No	Yes
Effector mechanisms	(1) Complement and other serum proteins; (2) Natural antibodies, produced by B1 lymphocytes; (3) Phagocytic cells (neutrophils, macrophages, dendritic cells); (4) Natural killer (NK) cells; (5) Local cells that respond to PAMPs by producing cytokines including interferons; (6) Apoptosis to remove infected cells; (7) Small interfering RNA molecules (RNAi) that interfere with virus replication	(1) Humoral response: different classes of antibodies produced by plasma cells derived from B lymphocytes; (2) Cell-mediated response: mediated by cytotoxic T lymphocytes (CTLs), usually CD8+; (3) Macrophages, especially after activation by cytokines such as IFN-γ released by antigen-specific T cells and NK cells

The innate response engages within minutes to hours. It depends on a fixed, germline-encoded repertoire of sensors and effectors and does not require any prior exposure to the virus. The adaptive response is antigen-specific, takes a week or more to assemble on first exposure, and generates immunological memory that accelerates and amplifies the response on re-encounter with the same virus.

Cells of the innate response

The cellular arm of the innate response is divided between phagocytes, cytotoxic cells, and sentinel cells.

Phagocytes

Macrophages. Tissue-resident phagocytic cells with characteristic names by location: Kupffer cells in the liver, alveolar macrophages in the lung, microglia in the central nervous system, Langerhans cells in the skin (technically of dendritic cell lineage), and splenic macrophages. They engulf virions and infected cell debris, produce inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-12), and present antigen to T cells. They are the dominant phagocyte by 24 hours after infection. Macrophage-derived cytokines drive the systemic signs of acute viral infection: IL-1 causes fever by acting on the hypothalamus, TNF-α causes cachexia in sustained infection (originally called cachectin), and IL-3 stimulates neutrophil production in the bone marrow.

Dendritic cells (DCs). The most efficient antigen-presenting cells and the critical bridge between innate and adaptive immunity. Plasmacytoid dendritic cells (pDCs) constitutively express high levels of TLR7, TLR9, and the transcription factor IRF7, and are the dominant producers of type I interferon in the body (up to a thousand times more per cell than other cell types). Conventional dendritic cells (cDCs) take up viral antigen at the portal of entry. Immature DCs are highly endocytic but poorly able to prime T cells. On detection of viral PAMPs through their pattern-recognition receptors, they mature: endocytic activity falls, surface MHC class II is upregulated, the costimulatory molecules CD80 (B7-1) and CD86 (B7-2) are induced, and the chemokine receptor CCR7 directs migration along CCL19 and CCL21 gradients to T cell zones of draining lymph nodes, where they prime naïve T cells. A specialised subset (cDC1 cells) can also load externally acquired viral antigen onto MHC class I, a process called cross-presentation, allowing CD8+ cytotoxic T cell priming against viruses that do not infect dendritic cells directly.

Neutrophils. Short-lived granulocytes recruited rapidly by the chemokine CXCL8 (IL-8). They engulf opsonised pathogens and release antimicrobial granule contents. Their role is more limited in viral than in bacterial infection.

Natural killer cells

Natural killer (NK) cells are large granular lymphocytes that share a developmental lineage with T cells but lack a clonally rearranged antigen receptor. They lyse virus-infected cells without prior sensitisation and act within the first one to two days of infection. Surface markers used to identify them include CD56 (the neural cell adhesion molecule, NCAM) and CD16 (the low-affinity IgG receptor, FcγRIII).

NK cell behaviour is governed by the balance between activating receptors (NKG2D, the natural cytotoxicity receptors NKp30, NKp44, and NKp46) and inhibitory receptors (the killer-cell immunoglobulin-like receptors, KIRs; and CD94 / NKG2A). Activating receptors recognise stress-induced ligands such as MICA, MICB, and the ULBP proteins, which are upregulated on infected or transformed cells. Inhibitory receptors recognise MHC class I molecules on the surface of healthy cells. The killing decision is set by the balance of these signals.

The missing-self hypothesis. In a healthy cell with normal MHC class I display, the inhibitory signal dominates and NK killing is switched off. Many viruses (notably the herpesviruses) downregulate MHC class I on the infected cell surface to escape recognition by CD8+ cytotoxic T cells. The loss of MHC class I removes the inhibitory signal to NK cells; the activating signals then dominate, and the NK cell kills the target. The hypothesis was proposed by Klas Kärre in 1986.

When activated, NK cells kill their targets by releasing preformed cytoplasmic granules containing perforin (which polymerises to form pores in the target cell plasma membrane) and granzyme B (a serine protease that enters through these pores and triggers caspase-mediated apoptosis). NK cells also recognise antibody-coated infected cells through CD16 binding to the Fc portion of IgG, triggering antibody-dependent cellular cytotoxicity (ADCC). Activated NK cells additionally produce IFN-γ, TNF-α, IL-4, and IL-13, which activate macrophages and shape the developing adaptive response, particularly Th1 polarisation.

Clinically, patients with primary NK cell deficiency develop disproportionately severe disease from herpes simplex virus, varicella-zoster virus, and human cytomegalovirus, reflecting NK cells’ particular importance in herpesvirus control and the herpesviruses’ common use of MHC class I downregulation as an evasion strategy.

Pattern recognition: PAMPs, DAMPs, and PRRs

The innate immune system has no way of recognising the unique antigens of any particular virus. It detects conserved molecular signatures common across whole classes of pathogens.

Pathogen-associated molecular patterns (PAMPs) are conserved molecular structures expressed by microbes and not by healthy host cells. For viruses, the major PAMPs are nucleic-acid structures that are either absent from healthy cells or present in unusual cellular 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 viral envelope glycoproteins and capsid proteins also act as PAMPs.

Damage-associated molecular patterns (DAMPs) are endogenous molecules released by stressed or dying host cells, including HMGB1 (a chromatin protein), ATP, uric acid, and heat-shock proteins. The same receptors that recognise PAMPs can detect many DAMPs, which is why infection and sterile injury can both trigger an innate response.

Pattern-recognition receptors (PRRs) are the host’s germline-encoded sensors. Four families are relevant to viral infection.

Toll-like receptors

Toll-like receptors (TLRs) were first identified in studies of the fruit fly (Drosophila spp.), and ten homologues have been described in humans. Each TLR recognises a different conserved molecular pattern.

TLR family	Other TLR members	Location	Ligand
1	2, 6, 10	Cell surface	Microbial cell walls (lipoproteins, peptidoglycans). TLR2 pairs with TLR1, TLR6, or TLR10 to form surface heterodimers
3		Endosome	Double-stranded RNA
4		Cell surface	Bacterial lipopolysaccharide
5		Cell surface	Bacterial flagellin
7	8, 9	Endosome	Single-stranded RNA (TLR7, TLR8); unmethylated CpG DNA (TLR9)
11	12, 13	Endosome	Toxoplasma gondii (TLR11, TLR12); bacterial ribosomal RNA (TLR13)

The viral-relevant TLRs sit on the endosomal membrane: TLR3 binds double-stranded RNA, TLR7 and TLR8 bind single-stranded RNA, and TLR9 binds unmethylated CpG DNA. Endosomal localisation matters because it allows discrimination between self and viral nucleic acids; the host’s own RNA and DNA do not normally reach the endosomal compartment.

TLR signalling diverges by adaptor protein. TLR3 signals through the adaptor TRIF, activating the kinases TBK1 and IKKε, phosphorylating IRF3, and inducing type I and type III interferon transcription. TLR7, TLR8, and TLR9 signal through MyD88, activating IRAK4 / IRAK1 / TRAF6, and phosphorylating IRF7 (which is constitutively expressed in plasmacytoid dendritic cells). NF-κB is activated in parallel along both pathways, driving transcription of inflammatory cytokines such as IL-6 and TNF-α.

Cytosolic RNA sensors

Two RIG-I-like receptors (RLRs) detect viral RNA in the cytoplasm. RIG-I (retinoic acid-inducible gene I) binds short double-stranded RNA carrying a 5’-triphosphate, a hallmark of many viral RNAs that is absent from host RNAs (which are 5’-capped). MDA5 (melanoma differentiation-associated protein 5) binds long double-stranded RNA. Both signal through the mitochondrial adaptor MAVS (mitochondrial antiviral signalling protein), which activates TBK1 and IKKε, phosphorylates IRF3, and induces type I and type III interferon transcription.

cGAS–STING

The cGAS–STING pathway is the principal cytosolic DNA-sensing pathway. 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: herpesvirus genomic DNA, reverse-transcription intermediates from retroviruses, mitochondrial DNA that has leaked out, or self-DNA fragments from damaged cells. Activated cGAS catalyses the synthesis of the cyclic dinucleotide 2’3’-cGAMP (cyclic GMP–AMP) from ATP and GTP. 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 TBK1, phosphorylates IRF3, and drives transcription of type I and type III interferons.

Genetic disorders of the pathway produce the type I interferonopathies, including Aicardi–Goutières syndrome, where impaired clearance of self-derived cytosolic nucleic acids leads to chronic interferon production and inflammatory disease.

NOD-like receptors and the inflammasome

NOD-like receptors (NLRs) are cytosolic sensors that assemble large multiprotein complexes called inflammasomes. The two NLRs most relevant to viral infection are NLRP3 (which responds to a broad set of stress signals including viral replication intermediates, mitochondrial dysfunction, reactive oxygen species, potassium efflux, and lysosomal rupture) and AIM2 (which binds cytosolic double-stranded DNA directly through a HIN200 domain).

On activation, the NLR sensor oligomerises and recruits the adaptor ASC and pro-caspase-1. Pro-caspase-1 self-cleaves to active caspase-1, which then cleaves three key substrates:

• Pro-IL-1β to mature IL-1β, a pyrogenic and inflammatory cytokine.
• Pro-IL-18 to mature IL-18, which amplifies IFN-γ production.
• Gasdermin D (GSDMD) is cleaved; its N-terminal fragment oligomerises and inserts into the plasma membrane, forming pores. The cell lyses (pyroptosis) and releases the cytokines into the inflammatory microenvironment.

Pyroptosis is the loud, inflammatory counterpart to apoptotic silent removal. It is a major driver of the severe inflammatory phenotype of influenza, hantavirus pulmonary syndrome, and severe COVID-19.

C-type lectins

C-type lectins recognise glycan moieties on viral surface proteins. DC-SIGN on dendritic cells and the mannose receptor on macrophages are the principal examples. They contribute to viral uptake by phagocytes and to dendritic cell-mediated antigen presentation, but some viruses exploit them as attachment receptors (HIV-1 and dengue virus both bind DC-SIGN).

The interferon system

Interferons (IFNs) are cytokines released by virus-infected cells that signal to neighbouring cells and to the wider immune system. They were first described in 1957 by Alick Isaacs and Jean Lindenmann, who showed that cells of the chorioallantoic membrane of embryonated hens’ eggs infected with influenza virus released a non-viral protein that protected fresh cells from infection by the same or an unrelated virus. They are classified into three types according to receptor usage.

The three types of interferon

	Type I	Type II	Type III
Examples	IFN-α (many species-specific subtypes); IFN-β (one type); IFN-δ, IFN-ε, IFN-κ, IFN-ο, IFN-τ	IFN-γ	IFN-λ1, IFN-λ2, IFN-λ3, IFN-λ4
Produced by	Most nucleated cell types	T cells and NK cells	Many cell types, but action restricted by receptor distribution
Receptor	IFNAR (a heterodimer of IFNAR-1 and IFNAR-2)	IFNGR (a tetramer of two IFNGR-1 / IFNGR-2 heterodimers)	IFNLR1 + IL-10R2, present mainly on melanocytes, hepatocytes, and epithelial cells
Effect of binding	Activates a cascade through TYK2 / JAK1 / STAT1 / STAT2 / IRF9 to form ISGF3, which binds interferon-stimulated response elements (ISREs) and induces interferon-stimulated genes (ISGs)	Activates a pathway through JAK1 / JAK2 / STAT1 to bind γ-activated sites (GAS) and induce a different gene set	Activates a JAK / STAT pathway, leading to ISG expression on the restricted cell types that express the receptor

Type I interferons (IFN-α, IFN-β) are the principal direct antiviral interferons. They are produced by almost any cell that detects intracellular viral infection and act on neighbouring cells through IFNAR. Plasmacytoid dendritic cells produce orders of magnitude more type I IFN per cell than other cell types. IFN-α has been used clinically in chronic hepatitis B and chronic hepatitis C, and IFN-β in relapsing multiple sclerosis.

Type II interferon is IFN-γ. It is not directly induced by arbitrary viral infection; it is produced by activated T cells (especially Th1 cells) and NK cells. Its principal role is to activate macrophages, recruit leukocytes, and amplify type I interferon effects. It is the major cytokine of cell-mediated immunity against intracellular pathogens.

Type III interferons (IFN-λ) use a receptor (IFNLR1) expressed predominantly on epithelial cells of the respiratory and gastrointestinal tracts, on hepatocytes, and on melanocytes. They act as a tissue-specific antiviral defence at mucosal surfaces and in the liver, with less of the systemic inflammation that accompanies type I IFN signalling. A single-nucleotide polymorphism in the IFN-λ3 / IFN-λ4 region is the strongest known host genetic predictor of spontaneous and treatment-induced clearance of hepatitis C virus infection.

JAK–STAT signalling and the antiviral state

When type I interferon binds IFNAR on a target cell, the receptor-associated kinases JAK1 and TYK2 phosphorylate STAT1 and STAT2, which heterodimerise with IRF9 to form the ISGF3 complex. ISGF3 translocates to the nucleus and binds interferon-stimulated response elements (ISREs) in the promoters of hundreds of interferon-stimulated genes (ISGs).

The cumulative effect is the antiviral state: the cell becomes resistant to productive viral infection, prepares to self-destruct if infected, signals its presence to NK cells, and upregulates antigen-presentation machinery for the developing adaptive response.

Key direct antiviral ISG effectors:

• Protein kinase R (PKR). Activated by double-stranded RNA. Phosphorylates the alpha subunit of eukaryotic initiation factor 2 (eIF-2α), shutting down all protein synthesis in the cell.
• 2’–5’ oligoadenylate synthetase (OAS) and RNase L. OAS is activated by dsRNA and produces 2’–5’ adenosine oligomers, which activate the latent endoribonuclease RNase L. RNase L cleaves all single-stranded RNA in the cytoplasm.
• Mx GTPases (MxA, MxB). Form oligomeric structures that trap viral nucleocapsids and block their nuclear import (active against influenza and hantaviruses; MxB also restricts HIV-1).
• Interferon-induced transmembrane proteins (IFITM1, IFITM2, IFITM3). Localise to late endosomal membranes and block fusion of enveloped viruses with host membranes (influenza, dengue, Zika, SARS-CoV-2).
• ISG15. A ubiquitin-like modifier that conjugates to host and viral proteins (ISGylation), with broad antiviral activity.
• Viperin / RSAD2. Disrupts the lipid raft assembly required by some enveloped viruses for budding.

Type II IFN-γ signals through STAT1 homodimers binding gamma- activated sites (GAS), inducing a partly overlapping gene set with macrophage activation as the central output. Type III interferons use a similar JAK / STAT cascade but on the restricted set of cells expressing IFNLR1.

Restriction factors

Restriction factors are host antiviral proteins constitutively 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.

• TRIM5α binds the incoming retroviral capsid and triggers premature uncoating and proteasomal degradation. Rhesus monkey TRIM5α is highly effective against HIV-1; the human version is less so, which is one reason HIV-1 successfully replicates in humans.
• APOBEC3G is a cytidine deaminase that introduces lethal G-to-A hypermutation into nascent retroviral DNA during reverse transcription. HIV Vif counteracts it by marking APOBEC3G for proteasomal degradation.
• Tetherin (BST-2) anchors at both ends of an enveloped virion’s lipid bilayer and physically holds budding virions on the cell membrane. HIV Vpu counteracts it by degrading tetherin (and also CD4).
• SAMHD1 is a dGTP-dependent triphosphohydrolase that depletes the cellular dNTP pool, starving reverse transcription. HIV-2 / SIV Vpx counteracts it by targeting it for degradation; HIV-1 lacks Vpx and is therefore restricted by SAMHD1 in myeloid cells and resting T cells.

Programmed cell death

Three forms of programmed cell death contribute to innate defence against viral infection.

Apoptosis is caspase-mediated programmed cell death. The cell shrinks, chromatin condenses, the plasma membrane stays intact until phagocytosis, and the dying cell is removed without releasing inflammatory contents. Two pathways converge on the effector caspases (3, 6, 7):

• The intrinsic (mitochondrial) pathway: cellular stress activates the BCL-2 family members BAX and BAK, which form pores in the mitochondrial outer membrane; cytochrome c leaks out, binds APAF-1 and pro-caspase-9 to form the apoptosome, which activates effector caspases.
• The extrinsic (death receptor) pathway: Fas, TNF receptor 1, and TRAIL receptor engagement assemble the death-inducing signalling complex (DISC), which activates caspase-8.

Many viruses block apoptosis to preserve their cellular replication factory: HSV ICP6 and CMV vICA both inhibit caspase-8; adenovirus E1B-19K mimics Bcl-2 to block the mitochondrial pathway.

Necroptosis is a programmed but lytic and inflammatory form of cell death, triggered when caspase-8 is blocked. RIPK1 and RIPK3 form the necrosome and phosphorylate the pseudokinase MLKL, which oligomerises and forms pores in the plasma membrane. Necroptosis releases DAMPs (HMGB1, ATP) that recruit further immune cells. The DNA sensor ZBP1 triggers necroptosis in influenza-infected cells. Necroptosis acts as a backup death pathway when a virus has disabled apoptosis.

Pyroptosis is inflammasome-driven, lytic, and highly inflammatory (described under NOD-like receptors above). Caspase-1 cleaves pro-IL-1β, pro-IL-18, and gasdermin D, releasing inflammatory cytokines and causing cell lysis through gasdermin D pore formation.

All three death programmes remove infected cells. Apoptosis is immunologically silent. Necroptosis and pyroptosis release DAMPs and pro-inflammatory cytokines that recruit further immune cells but also cause tissue injury.

Viral evasion of innate immunity

Most viruses of humans have evolved mechanisms to circumvent the innate immune response. The major strategies are summarised here; the Viral immune evasion article in this topic treats them in more detail with virus-specific catalogues.

Blocking pattern-recognition signalling. Hepatitis C virus encodes a protein (NS3 / 4A) that cleaves the cytosolic RNA sensor adaptor MAVS, shutting down interferon induction at the source. Picornavirus 3C proteases similarly cleave MAVS. Paramyxovirus V proteins target MDA5. Influenza A virus’s NS1 protein sequesters double-stranded RNA and inhibits RIG-I.

Interfering with interferon induction. Several gamma-herpesviruses downregulate the TLR3 adaptor TRIF. Paramyxovirus V protein additionally mimics IRF3 to prevent its activation. Poxvirus A49 blocks NF-κB.

Interfering with interferon signalling. Many viruses disrupt the JAK–STAT signalling cascade downstream of the interferon receptor. Dengue virus NS4B blocks JAK / STAT signalling. Paramyxovirus V proteins target STAT1 and STAT2 for degradation. Adenoviruses encode E1A, which sequesters STAT1.

Counter-restriction of host restriction factors. HIV Vif marks APOBEC3G for proteasomal degradation; HIV Vpu degrades tetherin; HIV-2 / SIV Vpx degrades SAMHD1.

Evasion of NK cell recognition. Five strategies are recognised:

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

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

Hijacking of cellular stress responses. Dengue virus exploits the unfolded protein response (UPR) for genome replication, and several flaviviruses and herpesviruses hijack autophagy machinery to support replication rather than to clear infection.

Subversion of dendritic cell function. Viruses such as HIV-1 and Ebola virus infect dendritic cells and break the link between innate and adaptive immunity. Ebola VP35 specifically blocks dendritic cell activation. Some viruses (poxviruses, herpesviruses) trigger dendritic cell apoptosis to limit antigen presentation.

Clinical correlates: when the innate arm fails

Genetic and acquired defects in components of the innate response produce specific patterns of viral disease that illustrate the role of each component in human defence.

Toll-like receptor 3 (TLR3) deficiency. Loss-of-function mutations in TLR3, or in its downstream signalling partners 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. The syndrome demonstrates that pattern-recognition pathways are not redundant: a single sensor can be essential for control of a specific virus at a specific anatomical site.

Type I interferon signalling defects. Mutations in STAT1, IFNAR1, or IFNAR2 produce severe disease from many viral infections, including overwhelming disease from live attenuated viral vaccines. Acquired neutralising autoantibodies against type I interferons account for around 15 per cent of severe COVID-19 cases in unvaccinated adults, a finding from 2020 to 2021 that confirmed the central role of the type I IFN system in defence against SARS-CoV-2.

NK cell deficiency. Primary NK cell deficiency presents with disproportionately severe disease from herpes simplex virus, varicella-zoster virus, and human cytomegalovirus.

References and recommended reading

• Burrell CJ, Howard CR, Murphy FA. Innate Immunity. In: Fenner and White’s Medical Virology, 5th edition, Chapter 5. Academic Press / Elsevier; 2017. The principal source for the anatomical and chemical barriers, the cells and pattern-recognition receptors of innate immunity, the interferon system, restriction factors and programmed cell death.
• Iwasaki A, Schoggins JW, Hur S. Innate Immunity to Viruses. In: Fields Virology, 7th edition, Chapter 9. Wolters Kluwer; 2023. Depth-of-field coverage of cGAS–STING, the inflammasomes, restriction factors, modern interferon biology and CD8 T cell exhaustion.
• Sompayrac LM. How the Immune System Works, 6th edition. Wiley-Blackwell; 2019. Plain-language explanations of the missing-self concept and other foundational ideas.