Mechanisms of viral inflammation and disease in humans

Abstract

Disease and accompanying inflammation are uncommon outcomes of viral infection in humans. Clinical inflammation occurs if steady-state cell-intrinsic and leukocytic immunity to viruses fails. Inflammation attests to the attempts of newly recruited and activated leukocytes to resolve infection in the blood or tissues. In the confusing battle between a myriad of viruses and cells, studies of human genetics can separate the root cause of inflammation and disease from its consequences. Single-gene inborn errors of cell-intrinsic or leukocytic immunity underlying diverse infections in the skin, brain, or lungs can help to clarify the human determinants of viral disease. The genetic elucidation of immunological deficits in a single patient with a specific vulnerability profile can reveal mechanisms of inflammation and disease that may be triggered by other causes, inherited or otherwise, in other patients. This human genetic dissection of viral infections is giving rise to a new biology and a new medicine.

Figure 1.. Inborn errors of immunity underlying severe cutaneous HPV infections.

Inborn errors of immunity underlying severe α/γ-HPV infection (red), β-HPV infection (blue), or both (in red/blue) are shown. Mutations impairing T-cell activation confer a predisposition to infections with α/γ-HPVs, which can underlie common warts or giant horns, and with β-HPVs, which can underlie flat warts or tinea versicolor-like lesions, and can progress to non-melanoma skin cancer. Inborn errors of immunity that impair the T-cell CD28 costimulation pathway (CD28, CARMIL2, CARD11, MAGT1) result in a predisposition to α/γ-HPV infections. EVER-CIB1 mutations impair keratinocyte-intrinsic immunity and confer a specific predisposition to infection with β-HPVs. GATA2 is not shown here because it is expressed by hematopoietic progenitors, and its deficiency can confer predisposition to both α/γ− and β-HPV infections due to progressive leukopenia. Inborn errors of immunity partially impairing TCR rearrangement (RAG1, RAG2, LIG4, NHEJ1, ATM, DCLRE1C, SMARCAL1) or T-cell differentiation (IL7, IL2RG, JAK3) are not shown, but can also underlie both α/γ- and β- HPV infections. APCs: antigen-presenting cells.

Figure 2.. Inborn errors of immunity of antiviral pathways underlying HSV-1 encephalitis.

Illustrations of the TLR3-type I IFN circuit and snoRNA31-dependent immunity in forebrain HSV-1 infection, and DBR1-mediated RNA lariat metabolism in brainstem viral infection. HSV-1 enters the forebrain and brainstem via the olfactory and trigeminal (TG) neurons, respectively. TLR3 controls basal levels of IFN-β-mediated anti-HSV-1 immunity in cortical neurons. TG neurons are susceptible to HSV-1 regardless of TLR3 genotype, whereas an exogenous TLR3 agonist or type I IFN renders healthy control TG neurons resistant to HSV-1 infection (35). DBR1 controls brainstem-specific immunity to viruses (HSV-1, influenza virus, norovirus), presumably in brainstem neurons. Genes for which mutations have been found to underlie forebrain HSV-1 encephalitis (red) or brainstem encephalitis (blue) are shown.

Figure 3.. Type I IFN immunity in viral pneumonia.

Type I IFN responses in influenza A virus (IAV) and SARS-CoV-2 infections of the lung. Type I IFNs are produced by plasmacytoid dendritic cells (which do not express TLR3) via an IRF7-dependent pathway, and by respiratory epithelial cells (which express TLR3) via a TLR3- and IRF7-dependent pathway. Inborn errors of immunity affecting these pathways can cause life-threatening pneumonia, including influenza pneumonia (IRF9, red), COVID-19 pneumonia (UNC93B1, TRIF, TBK1, IRF3, IFNAR1, and IFNAR2, blue), or both (TLR3 and IRF7, red/blue), whereas autoantibodies against type I IFN constitute a phenocopy of inborn errors of immunity of type I IFN that can cause life-threatening COVID-19 pneumonia. ISGs: interferon-stimulated genes.