Immunity and immunopathology to viruses: what decides the outcome?

Abstract

Many viruses infect humans and most are controlled satisfactorily by the immune system with limited damage to host tissues. Some viruses, however, do cause overt damage to the host, either in isolated cases or as a reaction that commonly occurs after infection. The outcome is influenced by properties of the infecting virus, the circumstances of infection and several factors controlled by the host. In this Review, we focus on host factors that influence the outcome of viral infection, including genetic susceptibility, the age of the host when infected, the dose and route of infection, the induction of anti-inflammatory cells and proteins, as well as the presence of concurrent infections and past exposure to cross-reactive agents.

Figure 1. Immunity or immunopathology following viral infection.

Following entry into host cells, viruses (cytopathic or non-cytopathic) replicate at the site of infection. Cytopathic viruses kill infected cells, causing the release of cellular contents, including proteases and lysosomal enzymes, which digest the extracellular matrix and create an inflammatory milieu. Neutrophils that are rapidly recruited to the site of infection release inflammatory mediators. Innate cells recognize viral replication intermediates and secrete pro-inflammatory cytokines, which, in addition to helping to clear the virus, contribute to tissue damage. Viral antigens are taken up by antigen-presenting cells and carried to local draining lymph nodes. Depending on the cytokine milieu created in the draining lymph node, different types of T helper (T_H) cell responses are induced. Primed CD8⁺ cytotoxic T lymphocytes (CTLs) migrate to the site of infection and kill virally infected cells, thereby contributing to tissue damage. After migrating to the site of infection, T_H cells also contribute to the tissue damage. In conditions in which the control of aggressive T_H cells and CTLs by regulatory T (T_Reg) cells is impaired and other inhibitory pathways fail to curtail them, tissue damage is the main consequence of viral infection. T_H cells also provide help to B cells to secrete antibodies, which form immune complexes that are deposited in certain tissues such as the glomeruli of the kidneys and blood vessels to cause immune complex-mediated disease. DAMP, danger-associated molecular pattern; DC, dendritic cell; HBV, hepatitis B virus; HCV, hepatitis C virus; HSV, herpes simplex virus; IFN, interferon; IL, interleukin; MMP, matrix metalloproteinase; NK, natural killer; PAMP, pathogen-associated molecular pattern; pDC, plasmacytoid DC; RNS, reactive nitrogen species; ROS, reactive oxygen species; RSV, respiratory syncytial virus; TCR, T cell receptor; T_FH, T follicular helper; TGFβ, transforming growth factor-β; TMEV, Theiler's murine encephalomyelitis virus; TNF, tumour necrosis factor.

Figure 2. Inhibitory mechanisms to limit tissue damage caused by T cells.

Effector T cells upregulate inhibitory receptors such as programmed cell death 1 (PD1), T cell immunoglobulin domain and mucin domain protein 3 (TIM3), lymphocyte activation gene 3 (LAG3) and cytotoxic T lymphocyte antigen 4 (CTLA4) (and others such as adenosine receptors (not shown)) on their surface. Ligation of these receptors with PDL1, galectin 9, MHC class II molecules and CD80 or CD86, respectively, delivers inhibitory signals to the effector T cells and controls their inflammatory activity and subsequent tissue damage. In addition, activated regulatory T (T_Reg) cells, specialized innate cells or highly polarized effector T cells that can produce anti-inflammatory cytokines inhibit effector T cell responses. Inadequate control exerted by these pathways under some circumstances therefore results in uncontrolled T cell activation and proliferation causing excessive tissue damage. Question marks indicate interactions for which extensive in vivo studies have not been carried out. IL-10; interleukin-10; TGFβ, transforming growth factor-β.

Figure 3. Balance between pro-inflammatory and anti-inflammatory mechanisms may decide the outcome of viral infection.

a | Pro-inflammatory and anti-inflammatory mechanisms induced after viral infection. b | The balance between immunity and immunopathology following viral infection might depend on the levels of anti-inflammatory and pro-inflammatory mechanisms. A balanced combination of pro-inflammatory and anti-inflammatory mechanisms would facilitate viral clearance and immunity to reinfection, with minimal damage to host tissues. An excess of pro-inflammatory mechanisms would ensure viral clearance but causes tissue damage. If anti-inflammatory mechanisms outweigh pro-inflammatory mechanisms, the pathogen could persist in the host as a subclinical infection, an opportunist or a tissue-damaging agent. CCL2, CC-chemokine ligand 2; CTLA4, cytotoxic T lymphocyte antigen 4; CXCL2, CXC-chemokine ligand 2; DUBA, deubiquitinase enzyme A; IFN, interferon; IL, interleukin; IRAKM, IL-1R-associated kinase M; LAG3, lymphocyte activation gene 3; NLRX1, NOD-like receptor X1; PD1, programmed cell death 1; RNF125, ring finger containing domain 125; RLR, RIG-I-like receptor; SOCS, suppressor of cytokine signalling; TGFβ, transforming growth factor-β; TIM3, T cell immunoglobulin domain and mucin domain protein 3; TLR, Toll-like receptor; TNF, tumour necrosis factor; T_Reg, regulatory T.