ABSTRACTAlthough the immune system is inherently designed to eliminate microbes, its development depends on its presence. The overall aim of this review is to highlight how hostmicrobe interactions, from commensal-derived signals to viral infections, shape immunity and influence both protective and pathological immune responses. Commensal microorganisms and their metabolic products have been shown to be indispensable for the maturation of the immune system. We demonstrated that peptidoglycan, a component of the Gram-negative bacterial cell wall, circulates in the blood of mice under steady-state conditions and is essential for maintaining normal hematopoiesis through the activation of the pattern recognition receptor NOD1 expressed in bone marrow mesenchymal stem cells. Moreover, NOD1 is expressed in peripheral lymphocytes, where it regulates their proliferation and survival by controlling the function of STAT5. The NOD-STAT5 axis is required to protect the host from protozoan infections. Therefore, NOD1 contributes to host protection by shaping the adaptive immune system. In addition to immunological homeostasis, understanding the immune responses to invading pathogens is important. During the COVID-19 pandemic, we showed that SARS-CoV-2 infects pulmonary endothelial cells and that non-classical macrophages recruit and produce thrombospondin-1, which promotes thrombosis, leading to impaired oxygenation and systemic deterioration. These lung thrombi contained platelet factor MYL9/12, and the serum level of MYL9 correlated with disease severity. Furthermore, we found that a subset of severe cases harbored autoantibodies against type I interferons, resulting in defective antiviral responses and poor viral control. These findings not only provide insight into the mechanisms of COVID-19 severity but also offer important perspectives against future viral pandemics.
Chiaki Iwamura (2026) studied this question.