Immune Response in COVID-19: Pathophysiology Mechanisms to Therapeutics
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The COVID-19 pandemic is rolling into its second year and continues to take its toll. Since December 2019, when the outbreak first emerged, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 153 million people and the resulting disease, COVID-19, has claimed more than 3.2 million lives, as of May 2021. The virus leverages the angiotensin-converting enzyme 2 (ACE2) receptor, which is widely expressed in the human body, to gain entry into cells. Thus, despite its name, the virus causes multi-organ damage beyond the lungs through viral tissue tropism as well as a multi-faceted pathophysiology, which encompasses immune system hyperactivity, microvascular damage and metabolic disturbances. Although it can be deadly at all ages, older individuals are especially vulnerable to SARS-CoV-2, and there is a higher risk of hospitalization, intensive care unit (ICU) admission and mortality with age. Furthermore, comorbidities, such as diabetes and cardiovascular disease, may also predispose COVID-19 patients to severe disease or death, and these conditions can be more prevalent in older individuals.
Immune system dysfunction has been a recurrent theme and active area of research throughout the pandemic. It is relevant to numerous facets of COVID-19, from disease pathophysiology and the so-called “cytokine storm” to the underlying reasons for higher mortality risk in older individuals. Additionally, there are multiple avenues of investigation for therapeutic development for COVID-19 via the immune system. This article will review the intersection between the COVID-19-induced cytokine storm with dysfunctional immune function in older age as well as leveraging the immune system for drug development.
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Immunosenescence and inflammaging: Fanning the flames
Although COVID-19 pathophysiology is complex and occurs through multiple pathways, immune system hyperactivity through cytokine storm is a prominent characteristic. “Cytokine storm is an umbrella term for the overproduction of proinflammatory cytokines in response to uncontrolled immune activation, including in response to infectious disease exposure,” explained Sean X. Leng, professor and geriatrician in the Division of Geriatric Medicine and Gerontology, Department of Medicine, Johns Hopkins University School of Medicine. “In COVID-19, cytokine storm manifests by elevation of C-reactive protein (CRP) and multiple proinflammatory cytokines, such as interleukin-6 (IL-6), which correlate with disease severity. Moreover, COVID-19 infection alters immune cell profiles; for instance, lymphopenia, a decrease in lymphocytes (T cells, B cells, natural killer [NK] cells), also correlates with disease seriousness.”
Leng is focused on elucidating how immune system characteristics of COVID-19 infection collude to increase risk in older populations. “Since the start of the pandemic, it was quite clear that advanced age was a significant risk factor for various adverse outcomes in COVID-19, from hospitalization or ICU admittance, to intubation, mortality, or composite scores,” elaborated Leng. “We’ve been interested in understanding what characteristics in older individuals predisposes them to severe infection. Through our effort, we developed what we term the “Immune Hypothesis” in COVID-19 infection,” he discussed of this work. Before the pandemic, Leng’s research was centered on immunity during infection, such as chronic cytomegalovirus infection and immunization to influenza in geriatric populations. “As we age, our immune system undergoes a remodeling process called immunosenescence.” These changes encompass decline in the function or reduction in the size of primary lymphoid tissues (e.g., thymus involution), which lowers the production of naïve T and B cells. Simultaneously, T cells express less CD28, a costimulatory surface receptor, impairing their function. Also, the immune repertoire contracts, shifting from naïve cells, which are capable of mounting an immune response to new infectious agents, to memory cells, which are only programmed to recognize previous encounters with infectious agents. Thus, the adaptive arm of the immune system ceases to function normally. In parallel, dysregulation also occurs in innate immunity, through a decline in macrophage and dendritic cell function.
“This breakdown in immune system function and decrease in innate and adaptive immune cells capable of mounting a defense has clinical ramifications for older individuals, particularly those who are frail within the oldest subset (e.g., octogenarians, nonagenarians and beyond). They become more susceptible to infections in general, including to SARS-CoV-2, and are more likely to suffer adverse outcomes,” explained Leng. Advanced age also creates a state called inflammaging, which is an integral part of immunosenescence and is characterized by chronic, low-grade inflammation. This inflammatory state in the geriatric population contributes to the development of many common age-related chronic conditions, such as dementia, cardiovascular diseases and disability. “Regarding COVID-19 infection, this inflammaging phenotype may prime older individuals to cytokine storm and worse outcomes. In our “Immune Hypothesis” of COVID-19 infection, we believe that, first, immunosenescence renders older individuals more susceptible to COVID-19 infections, and second, inflammaging makes them more likely to experience cytokine storm. Overall, this spells out a bad scenario for the geriatric population,” Leng explained.
Unfortunately, immunosenescence could also impact vaccine efficacy in older populations. “Although vaccine clinical trials claimed over 90% efficacy, even among older adults, they tended to be healthy and relatively young, i.e., less than 80 years old. My hypothesis is that these vaccines, despite using the new mRNA platform, may be less efficacious in older and frail patients,” Leng cautioned. “If older adults do contract COVID-19, there are a couple of promising therapies, based on the immune system. Recent studies have shown the benefit of the anti-inflammatory glucocorticoid dexamethasone. Convalescence plasma therapy, which is a passive immune therapy that passes on SARS-CoV-2-specific antibodies from someone who has had the infection, may also be beneficial, if initiated early and contains a high antibody titer.” Despite progress caring for COVID-19 patients as the pandemic continues, Leng believes it will be necessary to fill several knowledge gaps in the field to improve care further. “We still don’t know which key immune system components are critical to fighting SARS-CoV-2 successfully. We don’t know the key mechanisms the virus uses to replicate and spread inside the body, destroy cells and cause damage. It is even still unclear how the virus triggers cytokine storm, particularly in older adults, but also in children, the so-called “multisystem inflammatory syndrome-c” in rare cases.” Leng and his team continue their research to fill these gaps in the anticipation they will be able to provide better care to the geriatric population.
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Immune system therapies: Spreading hope
The realization that the immune system is involved in COVID-19 pathology has opened several avenues of investigation seeking to uncover mechanisms and potential therapeutic targets. Eric Vivier, professor at Aix Marseille Université and Hôpitaux Universitaires de Marseille in France was motivated to focus on just such research goals. “The pandemic really mobilized our efforts. We wanted to be part of the global effort to solve the problem. We are immunologists and have developed an expertise in the immune system and thought we could be helpful,” Vivier recalled of his decision to get involved.
“First, we needed to define the immune characteristics of COVID-19 patients. So, we profiled blood and bronchoalveolar lavage (BAL) fluid, meaning fluid from the lungs, from patients with COVID-19 infections of varying severity. This included patients that were paucisymptomatic, i.e., they had few symptoms, to those of intermediate severity with pneumonia, to the most severe cases with acute respiratory distress syndrome (ARDS). We were interested in identifying differences in immune profile by examining patients along the entire spectrum of disease severity,” Vivier explained of his methodology. “We noted that CRP and proinflammatory cytokine IL-6 correlated with disease seriousness, as well as multiple chemokines, CCL4 (macrophage inflammatory protein-1β), CCL2 (monocyte chemoattractant protein 1) and CXCL9 (monokine induced by interferon-γ). These cytokines and chemokines are generated by and influence myeloid cells, which prompted us to direct our attention on the complement system.”
The complement system (or cascade) is an arm of the innate immune system, which senses and clears pathogens. Part of this pathway is the complement fraction C5, which is cleaved into C5a and C5b; the latter combines with additional complement molecules to generate the membrane attack complex (MAC), a pore-forming structure, which lyses pathogens (Figure 1).
Figure 1. Membrane attack complex formation.
C5a binds to its receptor C5aR1, mediating strong chemoattraction and activation of myeloid cells. “Complement overactivation participates in inflammatory and immune diseases, which is very reminiscent of the inflammatory process in severe COVID-19 infection. In fact, complement component deposits had previously been detected in the lung epithelium of patients with other viral infections. Thus, we decided to focus on C5a in our study,” explained Vivier. He and his team went on to measure C5a plasma levels, which increased step-wise from paucisymptomatic, moderate, and severe COVID-19 patients. These findings were accompanied by additional key immune changes with progressively worse COVID-19 infection, including lymphopenia (decrease in lymphocytes), neutrophilia (increase in neutrophils) and a decrease in circulating inflammatory monocytes (CD14lowCD16+). “The decrease in inflammatory monocytes may arise because they leave the circulation to traffic into tissues,” explained Vivier. “Moreover, these circulating neutrophils and monocytes from COVID-19 patients expressed C5aR1 and produced IL-6, TNF, and CCL2, when they were exposed to recombinant C5a.”
When Vivier and his team examined BAL from COVID-19 patients with ARDS, they also found C5a deposition, confirming their hypothesis on complement involvement. Additionally, BAL from patients had elevated cytokines and an altered immune cell profile, which differed profoundly from healthy individuals. “This really implicated C5a in severe COVID-19 pathophysiology. So, we leveraged avdoralimab, an antibody that blocks the C5a–C5aR1 interaction, to evaluate whether it could block complement activation in the context of COVID-19. First, we found avdoralimab blocked C5a-induced neutrophil activation and migration and cytokine production from COVID-19 patient-derived monocytes in vitro. Second, avdoralimab also effectively inhibited C5a-induced acute lung injury in a human C5aR1 knock-in mouse model in vivo. Specifically, it lowered C5a-triggered CD45+, neutrophil, and monocyte immune cell infiltration into the lung and improved histological parameters.” Encouraged by these exciting findings, Vivier has launched a clinical trial to test avdoralimab in COVID-19 patients (NCT04371367). Vivier also published research on the role of NK cells in COVID-19 immune response. “We identified inhibitory immune checkpoints on natural killer cells. This is another exciting finding because there are well-tolerated immune checkpoint inhibitors to harness their function. Overall, we know that COVID-19 patients are in need of new therapies, and we hope our work will help contribute to an improved scientific understanding of this disease.”
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