Impact of MyD88 Deficiency on Innate Immune Function in COVID-19 Infection and Allotransplantation

The innate immune response is the first-line defense against infections. A large body of literature has demonstrated the critical role of MyD88, a toll-like receptor (TLR) adaptor protein in mediating innate immunity to invading microbes and modulating the adaptive immune response.1 Upon recognition of pathogen-associated molecular patterns or damage-associated molecular patterns, most TLRs signal through a canonical pathway involving the MyD88 adaptor protein and interleukin-1 receptor-associated kinase complex (IRAK), leading to downstream activation of NF-kB, and the release of inflammatory cytokines important for dendritic cell maturation and priming of naive T cells (Figure 1).2Figure 1.: TLR-MyD88 signaling pathway. Stimulation from PAMPs results in MyD88 complex formation with interleukin-1-receptor-associated kinase, downstream NF-kB activation, and inflammatory cytokine production. PAMP, pathogen-associated molecular pattern; TLR, toll-like receptor.Because of the expanding role of MyD88/IRAK-4 in proinflammatory cytokine signaling and in vitro literature demonstrating tempered host antiviral response with inhibition, MyD88 has been recognized as an attractive target in attenuating inflammatory disease states and for the understanding of host-virome responses.3 MyD88 deficiency has also been found to alter the expression of antimicrobial factors in mouse salivary glands. Humans with complete deficiency of MyD88 or IRAK-4 have impaired IgM recognition of T-independent microbial antigens, leading to increased susceptibility to invasive pyogenic bacterial infections.4 Surprisingly, severe viral and fungal infections have been rarely reported despite reduction in type 1 IFN responses by plasmacytoid dendritic cells (pDCs) in these individuals, possibly because of immunological redundancies and an intact adaptive immune response.5 Although abnormal responses to herpes simplex virus have been observed in both MyD88 and IRAK-4 deficient patients, those deficiencies have not resulted in an increased susceptibility to herpes simplex virus.6 Challenging this paradigm, a recent study in J Ex Med highlighted an increased risk for severe hypoxemic COVID-19 infections in patients with inherited MyD88 or IRAK-4 deficiency.7 Using a multinational cohort, Garcia-Garcia et al report on the clinical course of 22 unvaccinated COVID-19-infected patients with inherited MyD88, or IRAK-4 deficiencies. Compared with age-matched individuals from the general population, patients with MyD88/IRAK-4 deficiencies were more prone to severe forms of COVID-19 pneumonia with higher need for hospitalization, invasive mechanical ventilation, and increased mortality. Additionally, similar outcomes were seen in TLR7-deficient patients indicating that the susceptibility to severe COVID-19 respiratory infection is mediated through impaired TLR7-dependent viral sensing by pDCs. Because induction of Type I IFNs through TLR-3 was not affected in MyD88/IRAK-4 deficiency, findings concluded that Type I IFN by pDCs is TLR7 dependent on SARS-CoV-2 infection. Overall, the study highlights the involvement of MyD88 and IRAK-4 in TLR-mediated downstream T-cell regulation with substantial impact of these genetic deficiencies on the severity of COVID-19 infection in the unvaccinated population. These mechanisms of heightened host injury may have broader applications on the impact of dysregulated innate immunity on allograft tolerance and infections post-solid organ transplantation. Certain aberrancies in TLR signaling have been shown to be beneficial to allograft acceptance. Sentinel studies in skin transplant models have shown that the absence of MyD88 in the donor and/or recipient led to impaired inflammatory dendritic cell responses, reduced T-cell activation, and enhanced regulatory T cell-mediated suppression, promoting long-term allograft acceptance.8 Likewise, MyD88 deficiency was noted to be protective in experimental lung transplants. MyD88−/− mouse recipients of wild-type (WT) donor lung allografts had significantly reduced differentiated dendritic cells intragraft when compared with WT recipients; adoptive transfer of MyD88−/− monocytes into WT recipients showed that monocytes preferential differentiated into macrophages, whereas monocytes from WT predominantly differentiated into DCs, indicating the crucial need of MyD88 for alloantigen presentation.9 Similarly, MyD88-deficient mice have been shown to have a reduction in acute kidney allograft rejection.10 In contrast, dysfunctional TLR/MyD88/IRAK signaling may enhance infectious susceptibility. Although increased rates of severe viral infections have not been noted with MyD88/IRAK deficiencies, several case reports have noted augmented risks for specific viruses including influenza A, coronavirus NL63, and human herpesvirus 6.11 A recent study reported increased susceptibility to cytomegalovirus (CMV) disease in CMV D+/R− solid organ transplant recipients with specific single-nucleotide polymorphisms in several TLRs including 3, 4, 7, and 9. These polymorphisms were incorporated to develop a CMV polygenic score, identifying those at higher risk for CMV disease posttransplantation.12 Use of pharmacologic immunosuppression in transplant recipients aims to temper the adaptive immune response. Under these circumstances, innate immunity is vital for ongoing defenses against infections. Although the incidence of inherited TLR/MyD88/IRAK-4 axis deficiencies in transplant recipients or donors is not known, previous reports suggest that posttransplant immunosuppression such as cyclosporin and glucocorticoids can inhibit TLR-dependent activation of macrophages and alter DC differentiation and maturation.13 Based on these data, it is plausible that transplant recipients develop acquired innate immune dysfunction. The impact of COVID, influenza, and other community viral infections in transplant recipients has been disparate,14 and it is likely that both immunosuppression-related dysfunction and polymorphisms in TLR signaling can elevate the risk of opportunistic and community-acquired infections. These can have a direct impact on allograft health, especially in the lung, wherein viral infections are known to accelerate the risk for both acute and chronic allograft dysfunction.15 Overall, the impact of MyD88 deficiency on innate immune function in the context of SARS-CoV-2 and allotransplantation is complex and context dependent. An ongoing prospective observational trial (NCT03847285; clinicaltrials.gov) is evaluating the immune profile in SOTs to generate prediction models that may help identify risk for rejection and/or infectious complications. Results from this study may illuminate the role of underlying innate immune deficiencies on both allograft acceptance and infectious risk.