Tissue immunity to SARS-CoV-2: Role in protection and immunopathology

Abstract

The SARS-CoV-2 pandemic has demonstrated the importance of studying antiviral immunity within sites of infection to gain insights into mechanisms for immune protection and disease pathology. As SARS-CoV-2 is tropic to the respiratory tract, many studies of airway washes, lymph node aspirates, and postmortem lung tissue have revealed site-specific immune dynamics that are associated with the protection or immunopathology but are not readily observed in circulation. This review summarizes the growing body of work identifying immune processes in tissues and their interplay with immune responses in circulation during acute SARS-CoV-2 infection, severe disease, and memory persistence. Establishment of tissue resident immunity also may have implications for vaccination and the durability of immune memory and protection.

Keywords: lung immunity; lymph nodes; mucosal immunity; tissue resident memory cells.

FIGURE 1

Immune responses in tissues and circulation during acute infection and after resolution. A, Interplay of tissue and circulating responses during acute infection. In circulation, (left) infected individuals exhibit lymphopenia and neutrophilia; red blood cells (RBC) form microvascular clots. There is induction of virus‐specific antibodies, rapid production of inflammatory cytokines sometimes leading to cytokine storm, and enhanced levels of CD163⁺ monocytes (Mo) that are recruited to the lung. Lung tissue (top, left) demonstrates diffuse alveolar damage including areas of edema, hyaline membranes, and pneumocyte necrosis. The alveolar sac becomes filled with lymphocytes (T cells [T], B cells [B]), macrophages that interact with T cells and produce inflammatory cytokines, and neutrophils (PMN) that create neutrophil extracellular traps. Pathological fibroblasts (FB) appear to begin the tissue repair process. In lymph nodes (bottom, left) there is destruction of germinal centers and decreased lymphocytes; extra‐follicular T‐ and B‐cell interactions lead to the development of double negative (DN) B cells. B, Maintenance of immune memory in circulation and tissues. Following viral clearance and tissue repair, virus‐specific memory is maintained in the circulation and tissue sites including antibodies, CD4⁺ T cells, CD8⁺ T cells, and memory B cells. The alveolar sac in the lung (top, right) is cleared of immune cells, the alveolar cells (AT1/AT2) reform the epithelial barrier, and the lung parenchyma maintains tissue‐resident memory T and B cells (T_RM/B_RM). The lymph node (bottom, right) is also a major reservoir for virus‐specific memory, including persistent follicular responses with follicular helper T cells (T_FH) and germinal center B cells (GC B). Long lived plasma cells (PC) in circulation (also found in bone marrow) can maintain antibody titers

FIGURE 2

Considerations for inducing long‐term antiviral immune protection in circulation and tissues through immunization. Many different factors will affect the durability and localization of immune responses following vaccination, including vaccine formulation, method of administration, and a range of host factors such as age, will all collectively determine the immunogenicity of a vaccine response and its potential for generating long term protective immunity. While memory responses are most accessible to quantify in circulation, establishing productive follicular responses and robust tissue‐specific memory populations are critical in order to mitigate severe infection upon exposure to viral antigen following vaccination