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The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents the medical community with a significant challenge. COVID-19 is an entirely new disease with disparate clinical manifestations that are difficult to reconcile with a single pathogenic principle. Here, we explain how the flexible paradigm of the “damage-response framework” (DRF) of microbial pathogenesis can organize the varied manifestations of COVID-19 into a synthesis that accounts for differences in susceptibility of vulnerable populations as well as for differing manifestations of COVID-19 disease. The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents the medical community with a significant challenge. COVID-19 is an entirely new disease with disparate clinical manifestations that are difficult to reconcile with a single pathogenic principle. Here, we explain how the flexible paradigm of the “damage-response framework” (DRF) of microbial pathogenesis can organize the varied manifestations of COVID-19 into a synthesis that accounts for differences in susceptibility of vulnerable populations as well as for differing manifestations of COVID-19 disease. By focusing on mechanisms of host damage, particularly immune-mediated damage, the DRF provides a lens to understand COVID-19 pathogenesis and to consider how potential therapies could alter the outcome of this disease.

The state of latency occurs when a microbe's persistence in a host produces host damage without perturbing homeostasis sufficiently to cause clinical symptoms or disease. The mechanisms contributing to latency are diverse and depend on the nature of both the microbe and the host. Latency has advantages for both host and microbe. The host avoids progressive damage caused by interaction with the microbe that may translate into disease, and the microbe secures a stable niche in which to survive. Latency is clinically important because some latent microbes can be transmitted to other hosts, and it is associated with a risk for recrudescent microbial growth and development of disease. In addition, it can predispose the host to other diseases, such as malignancies. Hence, latency is a temporally unstable state with an eventual outcome that mainly depends on host immunity. Latency is an integral part of the pathogenic strategies of microbes that require human (and/or mammalian) hosts, including herpesviruses, retroviruses, Mycobacterium tuberculosis, and Toxoplasma gondii. However, latency is also an outcome of infection with environmental organisms such as Cryptococcus neoformans, which require no host in their replicative cycles. For most microbes that achieve latency, there is a need for a better understanding and more investigation of host and microbial mechanisms that result in this state.

Most patients with COVID-19 lack antibody to SARS-CoV-2 in the first 10 days of illness while the virus drives disease pathogenesis. SARS-CoV-2 antibody deficiency in the setting of a tissue viral burden suggests that using an antibody as a therapeutic agent would augment the antiviral immune response. In this issue of the JCI, Wang and collaborators describe the kinetics of viral load and the antibody responses of 23 individuals with COVID-19 experiencing mild and severe disease. The researchers found that (a) individuals with mild and severe disease produced neutralizing IgG to SARS-CoV-2 10 days after disease onset, (b) SARS-CoV-2 persisted longer in those with severe disease, and (c) there was cross-reactivity between antibodies to SARS-CoV-1 and SARS-CoV-2, but only antibodies from patients with COVID-19 neutralized SARS-CoV-2. These observations provide important information on the serological response to SARS-CoV-2 of hospitalized patients with COVID-19 that can inform the use of convalescent plasma therapy.

Antibody therapies such as convalescent plasma and monoclonal antibodies have emerged as major potential therapeutics for coronavirus disease 2019 (COVID-19). Immunoglobulins differ from conventional antimicrobial agents in that they mediate direct and indirect antimicrobial effects that work in concert with other components of the immune system. Antibody therapies such as convalescent plasma and monoclonal antibodies have emerged as major potential therapeutics for coronavirus disease 2019 (COVID-19). Immunoglobulins differ from conventional antimicrobial agents in that they mediate direct and indirect antimicrobial effects that work in concert with other components of the immune system. The field of infectious diseases pioneered antibody therapies in the first half of the 20th century but largely abandoned them with the arrival of conventional antimicrobial therapy. Consequently, much of the knowledge gained from the historical development and use of immunoglobulins such as serum and convalescent antibody therapies was forgotten; principles and practice governing their use were not taught to new generations of medical practitioners, and further development of this modality stalled. This became apparent during the COVID-19 pandemic in the spring of 2020 when convalescent plasma was initially deployed as salvage therapy in patients with severe disease. In retrospect, this was a stage of disease when it was less likely to be effective. Lessons of the past tell us that antibody therapy is most likely to be effective when used early in respiratory diseases. This article puts forth three principles of antibody therapy, namely, specificity, temporal, and quantitative principles, connoting that antibody efficacy requires the administration of specific antibody, given early in course of disease in sufficient amount. These principles are traced to the history of serum therapy for infectious diseases. The application of the specificity, temporal, and quantitative principles to COVID-19 is discussed in the context of current use of antibody therapy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Cryptococcosis occurs most frequently in immunocompromised individuals. This has led to the prevailing view that this disease is the result of weak immune responses that cannot control the fungus. However, increasingly, clinical and experimental studies have revealed that the host immune response can contribute to cryptococcal pathogenesis, including the recent study of L. M. Neal et al. (mBio 8:e01415-17, 2017, https://doi.org/10.1128/mBio.01415-17 ) that reports that CD4 + T cells mediate tissue damage in experimental murine cryptococcosis. This finding has fundamental implications for our understanding of the pathogenesis of cryptococcal disease; it helps explain why immunotherapy has been largely unsuccessful in treatment and provides insight into the paradoxical observation that HIV-associated cryptococcosis may have a better prognosis than cryptococcosis in those with no known immune impairment. The demonstration that host-mediated damage can drive cryptococcal disease provides proof of concept that the parabola put forth in the damage-response framework has the flexibility to depict complex and changing outcomes of host-microbe interaction.

5 Additionally, the real-world treatment of patients with COVID-19 is complicated by recurrent fevers, fluctuating oxygen requirements, prolonged hospitalization and/or ventilation, blurring the line between community-acquired versus hospital-acquired pneumonia. [...]we sought to determine the prevalence of MRSA in respiratory cultures of patients admitted with COVID-19, and we evaluated the diagnostic performance of the MRSA nares PCR test, a valuable stewardship tool for ruling out MRSA pneumonia in low-prevalence settings,6 in this cohort. Prevalence of Methicillin-Resistant Staphylococcus aureus (MRSA) in Respiratory Cultures at Different Time Points of Hospital Stay Days from Admission Day 3 Day 7 Day 14 Day 28 Total patients with respiratory cultures obtained, no. 158 285 405 472 Patients with MRSA in respiratory cultures, no 1 7 18 27 Prevalence, % 0.6 2.4 4.4 5.7 Also, 369 MRSA nares PCR tests were performed among the patients in the cohort; of these patients, 122 had corresponding respiratory cultures within 5 days of the PCR test. Clinicians should remain guided by local epidemiologic data; notably, however, the Bronx has had the highest rates of MRSA infections in New York City.7 Additionally, our findings are in keeping with decreasing rates of MRSA infections across the United States in recent years.8,9 Given the low prevalence, we found excellent diagnostic performance of the MRSA nares PCR test, with 100% negative predictive value, confirming that the MRSA nares PCR test remains an important stewardship tool to guide discontinuation of anti-MRSA antibiotics, if started empirically for pneumonia in patients with COVID-19.

The view that immunoglobulins function largely by potentiating neutralization, cytotoxicity or phagocytosis is being replaced by a new synthesis whereby antibodies participate in all aspects of the immune response, from protecting the host at the earliest time of encounter with a microbe to later challenges. Perhaps the most transformative concept is that immunoglobulins manifest emergent properties, from their structure and function as individual molecules to their interactions with microbial targets and the host immune system. Given that emergent properties are neither reducible to first principles nor predictable, there is a need for new conceptual approaches for understanding antibody function and mechanisms of antibody immunity.

Key Points Passive antibody therapy is not a new technique. Behring and Kitasato discovered that specific antibodies could protect against bacterial toxins in the early 1890s and, by the 1930s, serum therapy was being widely used to treat a variety of infectious diseases. However, the increase in the popularity of serum therapy occurred at about the same time as the first antibiotics were developed, and as antibiotics became more widely available, so the use of serum therapy declined. By the late 1940s it had largely been abandoned. In recent years there has been renewed interest in using passive antibody therapy to treat infectious diseases. However, at present, although immunoglobulin preparations are available to treat some infections, such as hepatitis B, rabies and varicella–zoster virus, only one monoclonal antibody (palivizumab) has been licensed to prevent an infectious disease. The advantages of using antibody molecules to treat infectious diseases include their specificity and versatility. Antibodies are capable of mediating a variety of different biological effects including both those that are independent of other components of the host immune system, such as neutralizing toxins and viruses and activating complement, and effects that involve other components of the host immune system, such as antibody-dependent cellular cytotoxicity and opsonization. Additionally, the effects of antibodies can be synergistic with those of conventional antimicrobial therapies, and the time to develop therapeutic antibody preparations would be considerably shorter than the development time for a vaccine. One of the most important advantages of using antibodies is that they can be easily modified to target host cells. One such strategy is radioimmunotherapy, in which a radionuclide is attached to an antibody molecule. As an intact immune system is not required, radioimmunotherapy could be particularly effective in immunocompromised hosts. As infected cells can be killed by a 'crossfire' effect, radioimmunotherapy might also be useful to target intracellular pathogens and chronic infections. The high specificity of antibodies can also be a disadvantage when considering antibody-based therapies because accurate diagnosis of the causative microbial agent of an infection is necessary and a 'cocktail' of different antibodies might be required to treat infections with a microorganism that undergoes antigenic variation. As the efficacy of therapeutic antibody preparations decreases with time, this might mean that they are best applied to infections where early diagnosis is possible. Additionally, the costs associated with antibody treatments can be higher than treatment with conventional antimicrobial agents; however, the increased costs of the treatment should be offset against the lower rates of resistance associated with antibody therapy. Antibody-based therapies are currently undergoing a renaissance. After being developed and then largely abandoned in the twentieth century, many antibody preparations are now in clinical use. However, most of the reagents that are available target non-infectious diseases. Interest in using antibodies to treat infectious diseases is now being fuelled by the wide dissemination of drug-resistant microorganisms, the emergence of new microorganisms, the relative inefficacy of antimicrobial drugs in immunocompromised hosts and the fact that antibody-based therapies are the only means to provide immediate immunity against biological weapons. Given the need for new antimicrobial therapies and many recent technological advances in the field of immunoglobulin research, there is considerable optimism regarding renewed applications of antibody-based therapy for the prevention and treatment of infectious diseases.

Transfer of convalescent plasma (CP) had been proposed early during the SARS-CoV-2 pandemic as an accessible therapy, yet trial results worldwide have been mixed, potentially due to the heterogeneous nature of CP. Here we perform deep profiling of SARS-CoV-2-specific antibody titer, Fc-receptor binding, and Fc-mediated functional assays in CP units, as well as in plasma from hospitalized COVID-19 patients before and after CP administration. The profiling results show that, although all recipients exhibit expanded SARS-CoV-2-specific humoral immune responses, CP units contain more functional antibodies than recipient plasma. Meanwhile, CP functional profiles influence the evolution of recipient humoral immunity in conjuncture with the recipient’s pre-existing SARS-CoV2-specific antibody titers: CP-derived SARS-CoV-2 nucleocapsid-specific antibody functions are associated with muted humoral immune evolution in patients with high titer anti-spike IgG. Our data thus provide insights into the unexpected impact of CP-derived functional anti-spike and anti-nucleocapsid antibodies on the evolution of SARS-CoV-2-specific response following severe infection. Convalescent plasma (CP) has been trialed as a therapy for SARS-CoV-2 symptoms, but its heterogenous nature precludes uniform outcomes. Here the authors perform deep profiling of CP, as well as plasma of CP recipients before and after transfer, to find CP-mediated, spike/nucleocapsid-focused modulations of humoral responses in the recipient.