One of the important determinants of severe Covid-19 appears to be an inappropriate response by the innate immune system. Specifically, this involves, on the one hand, insufficient or delayed expression and signaling by type 1 interferons (IFNs), which induce innate cell-mediated immunity. The interferon (IFN) response constitutes the major first line of defense against viruses. On the other hand, this involves an overly active inflammatory cytokine response, with its attendant tissue damage (this “cytokine storm” was explored in our previous Perspective at https://gvn.org/category/sars-cov-2/gvn-sars-cov-2-perspectives/). Let’s look at some of the lines of evidence for these contradictory events.
One way in which an aberrant immune response to SARS-CoV-2 is reflected at the cellular level is by a greatly increased ratio of neutrophils to lymphocytes(1). This is correlated with low expression of type I and III interferons and high expression of pro-inflammatory factors including IL-6 and a variety of chemokines(2) that act as attractants for neutrophils and monocyte/macrophages. These activities are the outcome of interactions between host factors that recognize pathogen associated molecular patterns (PAMPs), such as viral RNA in endosomes, and viral proteins that are antagonistic to these factors and their signaling pathways. Genetic differences in host factors can result in profound differences in host responses to pathogens (recent findings are described below). Different viruses also tend to have different or unique antagonists to host immune factors that can greatly influence the outcome of infection.
What are some of the molecular studies that point to defects in interferon activity in severe Covid-19? Recently, interest has been increasing in toll-like receptors (TLRs), especially TLR3 and TLR7, which recognize viral RNA and are important in interferon type I and inflammatory cytokine expression. TLRs play a key role in the recognition of PAMPs and trigger the activation of specific signaling pathways, thereby inducing the transcription of inflammatory and/or anti-inflammatory cytokine. One interesting report looked at two sets of two brothers(3) who, although young and otherwise healthy, had severe Covid-19 (one died). Whole exome sequencing revealed that both sets of brothers had mutations in TLR7, which serves as a sensor for viral RNA. One set had a missense mutation predicted to result in an inactive TLR7, while the other set had a frame shifting 4 nucleotide deletion, resulting in a nonsense protein. Stimulation of primary immune cells in vitro with the TLR agonist imiquimod resulted in defective expression of type I interferon-related genes normally regulated by TLR7. While the limited nature of the study does not permit a conclusion of causality, several factors make it likely that these loss of function mutations are significant. Exhibition of severe disease in young men is rare. Despite rare cases of loss of function mutations in TLR7, two different loss of function mutations in two young brother pairs with severe disease indicate its potential role in Covid-19 severity. It should be pointed out that TLR7 is located on the X chromosome, so a single mutant copy would cause loss of function. One of the mothers was heterozygous for wild type TLR7, making her a carrier. Thus, if problems with the TLR7 pathway exacerbate Covid-19, males might be likelier to have an insufficiency.
Another study analyzed the complete genomes or exomes of 659 patients with life threatening Covid-19 and compared them with those of 534 people with asymptomatic or benign infections(4). They characterized 13 genetic loci encoding factors in the TLR3-interferon regulatory factor 7 (IRF7) pathway, which also regulates type I interferon production and immunity to influenza virus. They found that 3.5% of the people with life threatening Covid-19 had loss of function variants at these loci. Moreover, when immune cells from patients with these variants were tested in vitro, they were found to be defective in type-I interferon immune activities, and further in vivo study confirmed impaired production of type I IFN during the course of SARS-CoV-2 infection. About half of these patients also had extremely low levels of serum interferon α, a type I interferon.
Yet, another study further implicates lack of appropriate interferon activity in severe Covid-19(5). In this study, 101 of 987 patients with life threatening Covid-19 had auto-antibodies against interferon α, interferon ω or both. These were not present in 663 patients with mild disease. The auto-antibodies were able to neutralize the antiviral effects of interferon in vitro (and likely in vivo). Interestingly, the auto-antibodies were about 5-fold more prevalent in men than in women.
None of these studies by themselves show a specific defect in interferon activity in a majority of cases. However, taken together, they certainly suggest that a great variety of different defects related to the antiviral activities of type 1 interferons may be surprisingly common. Probably, one of the factors explains why some people resist serious disease while, for others, it is life-threatening. Further, investigations in this area will be most interesting.
One other study identified a 3p21.31 gene cluster that conferred a risk of severe Covid-19. This region contains three chemokine receptor genes, all involved in innate immunity(6). It turns out to be a region derived from Neanderthals, and is present at variable incidence worldwide except in Africa. This provides yet another clue that the innate immune response to SARS-CoV-2 may be an important determinant of whether an infected individual will, or will not, develop critical Covid-19.
In this light, it has been proposed that some cross-protection could be afforded by administering live attenuated vaccines, such as measles-mumps-rubella, and oral polio vaccine(7) (non-specific effect of vaccination against SARS-CoV-2). The stimulation of innate immunity by these vaccines could provide temporary protection against Covid-19. If proven to be effective against Covid-19, emergency immunization with these vaccines could be used for protection against other unrelated emerging pathogens.
- Y. Liu et al., Neutrophil-to-lymphocyte ratio as an independent risk factor for mortality in hospitalized patients with COVID-19. J Infect 81, e6-e12 (2020).
- D. Blanco-Melo et al., Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell 181, 1036-1045 e1039 (2020).
- C. I. van der Made et al., Presence of Genetic Variants Among Young Men With Severe COVID-19. JAMA 324, 663-673 (2020).
- Q. Zhang et al., Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science, (2020).
- P. Bastard et al., Auto-antibodies against type I IFNs in patients with life-threatening COVID-19. Science, (2020).
- D. Ellinghaus et al., Genomewide Association Study of Severe Covid-19 with Respiratory Failure. N Engl J Med, (2020).
- K. Chumakov, C. S. Benn, P. Aaby, S. Kottilil, R. Gallo, Can existing live vaccines prevent COVID-19? Science 368, 1187-1188 (2020).