It is well understood that the adaptive immune response to infectious agents includes a modulating suppressive component as well as an activating component. We now show that the very early innate response also has an immunosuppressive component. Infected cells upregulate the CD47 “don’t eat me” signal, which slows the phagocytic uptake of dying and viable cells as well as downstream antigen-presenting cell (APC) functions. A CD47 mimic that acts as an essential virulence factor is encoded by all poxviruses, but CD47 expression on infected cells was found to be upregulated even by pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that encode no mimic. CD47 upregulation was revealed to be a host response induced by the stimulation of both endosomal and cytosolic pathogen recognition receptors (PRRs). Furthermore, proinflammatory cytokines, including those found in the plasma of hepatitis C patients, upregulated CD47 on uninfected dendritic cells, thereby linking innate modulation with downstream adaptive immune responses. Indeed, results from antibody-mediated CD47 blockade experiments as well as CD47 knockout mice revealed an immunosuppressive role for CD47 during infections with lymphocytic choriomeningitis virus and Mycobacterium tuberculosis. Since CD47 blockade operates at the level of pattern recognition receptors rather than at a pathogen or antigen-specific level, these findings identify CD47 as a novel potential immunotherapeutic target for the enhancement of immune responses to a broad range of infectious agents. IMPORTANCE Immune responses to infectious agents are initiated when a pathogen or its components bind to pattern recognition receptors (PRRs). PRR binding sets off a cascade of events that activates immune responses. We now show that, in addition to activating immune responses, PRR signaling also initiates an immunosuppressive response, probably to limit inflammation. The importance of the current findings is that blockade of immunomodulatory signaling, which is mediated by the upregulation of the CD47 molecule, can lead to enhanced immune responses to any pathogen that triggers PRR signaling. Since most or all pathogens trigger PRRs, CD47 blockade could be used to speed up and strengthen both innate and adaptive immune responses when medically indicated. Such immunotherapy could be done without a requirement for knowing the HLA type of the individual, the specific antigens of the pathogen, or, in the case of bacterial infections, the antimicrobial resistance profile.

Vaccination induced antibody and T-cell immune responses are important for systemic protection from COVID-19. Because SARS-CoV-2 infects and is transmitted by oral-pharyngeal mucosa, we wished to test mucosal antibodies elicited by natural infection or intramuscular vaccine injection. In a non-randomized observational study, we measured antibodies against the SARS-CoV-2 RBD in plasma and saliva from convalescent or vaccinated individuals and tested their neutralizing potential using a replication competent rVSV-eGFP-SARS-CoV-2. We found IgG and IgA anti-RBD antibodies as well as neutralizing activity in convalescent plasma and saliva. Two doses of mRNA vaccination (BNT162b2 or mRNA-1273) induced high levels of IgG anti-RBD in saliva, a subset of whom also had IgA, and significant neutralizing activity. We detected anti-RBD IgG and IgA with significant neutralizing potential in the plasma of single dose Ad26.COV2.S vaccinated individuals, and we detected slight amounts of anti-RBD antibodies in matched saliva. The role of salivary antibodies in protection against SARS-CoV-2 infection is unknown and merits further investigation. This study was not designed to, nor did it study the full kinetics of the antibody response or protection from infection, nor did it address variants of SARS-CoV-2.

COVID-19 has generated a rapidly evolving field of research, with the global scientific community striving for solutions to the current pandemic. Characterising humoral responses towards SARS-CoV-2, as well as closely related strains, will help determine whether antibodies are central to infection control, and aid the design of therapeutics and vaccine candidates. This review outlines the major aspects of SARS-CoV-2-specific antibody research to date, with a focus on the various prophylactic and therapeutic uses of antibodies to alleviate disease in addition to the potential of cross-reactive therapies and the implications of long-term immunity.

COVID-19 was initially characterised as a disease primarily of the lungs, but it is becoming increasingly clear that the SARS-CoV2 virus is able to infect many organs and cause a broad pathological response. The primary infection site is likely to be a mucosal surface, mainly the lungs or the intestine, where epithelial cells can be infected with virus. Whilst it is clear that virus within the lungs can cause severe pathology, driven by an exaggerated immune response, infection within the intestine generally seems to cause minor or no symptoms. In this review we compare the disease processes between the lungs and gastrointestinal tract, and what might drive these different responses. As the microbiome is a key part of mucosal barrier sites, we also consider the effect that microbial species may play on infection and the subsequent immune responses. Due to difficulties obtaining tissue samples there are currently few studies focused on the local mucosal response rather than the systemic response, but understanding the local immune response will become increasingly important for understanding the mechanisms of disease in order to develop better treatments.

Lyme disease, caused by the bacteria Borrelia burgdorferi, is the most common and rapidly growing vector-borne infectious disease in the United States and Europe. High variability in disease burden among Lyme patients suggests that individual immune responses may be key drivers of clinical presentation and patient outcomes. Use of high resolution flow-based immunosorbent profiling revealed that a subset of Lyme patients with persistent symptoms were producing high concentrations of IgE specific to B. burgdorferi. Comparing C57B/6 mice, which are tolerant to B. burgdorferi, and C3H/HeJ mice, which are susceptible to disease, we find high levels of IgE specific for B. burgdorferi in C3H/HeJ but not C57B/6 mice. Furthermore, IgE was found to target Borrelia peptidoglycan in both acute and chronic infection models. Histologic analysis of mouse Lyme arthritic ankle tissue showed mast cells, which release highly immunogenic effectors upon activation by bound IgE, degranulating at significantly higher rates compared to uninfected controls. Forced mast cell degranulation exacerbated Lyme arthritis in infected mice. This data suggests that a subset of Lyme patients with persistent symptoms may have developed an allergic response to conserved bacterial antigens from a B. burgdorferi infection, as opposed to an autoimmune type response. Inclusion of IgE reactivity in diagnostic testing and examination of pathological immune responses to bacterial antigens could assist clinicians in patient care and effective treatments. Research reported in this publication was supported by the Fairbairn family foundation; Bay Area Lyme Foundation; the Younger family foundation; the Robert J. Kleberg, Jr., and Helen C. Kleberg Foundation; the Virginia and D. K. Ludwig Fund for Cancer Research; M.C.T. was supported by Stanford Immunology training grant 5T32AI007290, and the NIH NRSA 1 F32 AI124558-01 award. L.B.T.D. was supported by a Stanford Diversifying Academia Recruiting Excellence fellowship. S.D.G was supported by the California Institute for Regenerative Medicine Bridges 2.0 Training Program grant EDUC2-08397. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.