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Is Innate Immunity Our Best Weapon for Flattening the Curve?

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Is Innate Immunity Our Best Weapon for Flattening the Curve? VIEWPOINT The Journal of Clinical Investigation Is innate immunity our best weapon for flattening the curve? Leonard Angka,1,2 Marisa Market,1,2 Michele Ardolino,1,2,3 and Rebecca C. Auer1,4 1Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. 2Department of Biochemistry, Microbiology, and Immunology, 3Centre for Infection, Immunity, and Inflammation, and 4Division of General Surgery, Department of Surgery, University of Ottawa, Ottawa, Ontario, Canada. The COVID-19 pandemic is a stern re­ Ideally, alternative strategies to social penia, and a protracted clinical course (6). minder not to take our immune system for distancing should (a) still protect high­ These similarities should raise a caution­ granted. The fact that some individuals con­ risk individuals, (b) accelerate the glob­ ary flag, since humoral responses against tract and clear the SARS–CoV-2 virus without al recovery, and (c) easily be adapted to this feline coronavirus, rather than being apparent symptoms stands in sharp contrast tackle future pandemics. Here, we move protective, result in a more severe disease to the damage that this virus has brought forward the hypothesis that harnessing course. In these cases, subneutralizing lev­ upon more vulnerable populations, including innate immunity is our best weapon for els of spike S protein antibodies opsonize the elderly and patients with chronic con­ fighting novel viral outbreaks by prevent­ the virus and promote infection of immune ditions or cancer. While the differences in ing a productive infection or by accelerat­ cells expressing Fc receptors (antibody­de­ severity of infection between these popula­ ing viral clearance. pendent enhancement of disease). It is tions are multifactorial, it is likely that innate Active immunization provides pro­ likely that current vaccine endeavors will immunity provides the underpinning, given tection against a specific vaccination tar­ overcome these barriers, but this will take its central role in the early response to viral get through antigen­specific responses time and the vaccine may be ineffective infections. Within two decades, there have by adaptive lymphocytes. An effective against future coronaviruses (7). been three known coronavirus zoonoses antigen­specific vaccine can completely An intriguing alternate strategy to (SARS–CoV-1, MERS, and SARS–CoV-2), all protect the majority of healthy individu­ vaccination relies on enhancing innate of which have taken a devastating toll on the als, so it is not surprising that the world is immunity, which has been successfully human and economic health of affected soci­ waiting for this panacea with bated breath. adopted in veterinary medicine to prevent eties. Unfortunately, with the frequency and It is important to remember, however, that the transmission of respiratory viruses in diffusion of novel zoonoses, this is unlikely human endemic coronaviruses, which cattle housed in close quarters (8). Spe­ to be our last battle. As we begin the long and are responsible for up to 35% of common cifically, administration of an inactivated daunting recovery from this pandemic, we colds, often reinfect individuals, some­ Parapoxvirus ovis virus broadly activates must take the opportunity to think about how times even in the same year (2), despite innate immune components, including to exploit our innate immune system to better 90% of individuals developing corona­ dendritic cells, NK cells, and type I IFNs, prepare us to fight the next virus. virus­specific antibodies (3). Even when and protects livestock from many respira­ infection yields high antibody titers, the tory illnesses unrelated to Parapoxvirus. Harnessing innate immunity titer half­life is, in some cases, short (4). Innate immunity acts as our body’s “One may know how to conquer without Further undermining the hope for an front­line troops. Pattern­recognition being able to do it” (1). effective respiratory/coronavirus vaccine receptors recognize viral components and In most countries, interventions have been are examples from veterinary medicine, prompt IFN production. IFNs have direct put in place to flatten the curve. The goal where coronaviruses are scourges that antiviral activity and choreograph the of these interventions is to slow the spread have eluded eradication despite vaccina­ innate and adaptive lymphocyte respons­ of the virus so that capacity of medical tion. This is surely not for a lack of trying, es. They are so central to antiviral respons­ resources, such as hospital beds, ventilators, as bovine coronaviruses cause several dis­ es that zoonotic coronaviruses dedicate and personal protective equipment, is not eases, including shipping fever: a deadly much of their genome to suppressing them exceeded and we can adequately care for respiratory disease common in commer­ (9), lending credence to the hypothesis the sick. While social distancing has proven cial feedlots that is responsible for an that prophylactic or early IFN treatment highly effective in flattening the curve, it is estimated loss of $900 million annually will circumvent immune evasion and often impossible for essential workers or vul­ (5). Another example is the highly lethal promote viral clearance (10). Based on nerable patients. Moreover, the ripple effects feline coronavirus, which shares similari­ this rationale, clinical trials with recom­ of social distancing on our economy and ties to SARS–CoV-1/2, including viral per­ binant IFNs are underway. One clinical well­being are not sustainable long term. sistence, induction of profound lympho­ trial (ClinicalTrials.gov NCT04320238) is using nasally administered recombinant IFN­α1β to prevent SARS–CoV-2 infection Authorship note: LA and MM contributed equally. MA and RCA contributed equally. among medical workers. A second clinical Conflict of interest: The authors have declared that no conflict of interest exists. Copyright: © 2020, American Society for Clinical Investigation. trial (NCT04293887) will administer IFN­ Reference information: J Clin Invest. 2020;130(8):3954–3956. https://doi.org/10.1172/JCI140530. α1β to newly diagnosed patients within 7 3954 jci.org Volume 130 Number 8 August 2020 The Journal of Clinical Investigation VIEWPOINT days of symptoms onset, while a third trial against COVID-19. Unfortunately, BCG infected cells, and present higher expres­ (NCT04331899) will treat mild COVID-19 is contraindicated in many vulnerable sion of inhibitory receptors, e.g., NKG2A, cases with type III IFN, which has partially patients, such as those undergoing chemo­ which increases the threshold of activa­ overlapping functions, but reduced toxici­ therapy. However, the IMM-101 vaccine tion for NK cells (19). However, in more ty compared with type I IFN. If successful, (heat­killed Mycobacterium obuense) has severe COVID-19 infections, myeloid these trials will provide the proof of con­ a mechanism of action similar to that of cells accumulate in the lungs and pro­ cept that prophylactic/early stimulation of BCG, with an established safety profile in mote the recruitment and activation of the innate immune system provides pro­ cancer patients (16). The Canadian Cancer lymphocytes, including NK cells. Once in tection against SARS–CoV-2 and, in theo­ Trials Group has proposed testing IMM­ the lungs, NK cells are likely to be among ry, against future coronaviruses. 101 in a clinical trial to protect high­risk the main producers of IFN­γ, which con­ cancer patients who cannot self­isolate tributes to immunopathology and the Training innate immunity due to their treatment (CCTG ID IC8). development of acute respiratory distress “He who is prudent and lies in wait for an When considering the mechanism of syndrome (20). enemy who is not, will be victorious” (1). action of IFNs and heterologous vaccines, The discordance in our assertions that Like any army, our innate immune sys­ NK cells emerge as important mediators of innate immunity eradicates COVID-19 tem will respond more effectively when the therapeutic response. NK cells are key while having a pathological role in severe primed. Recent studies have highlighted components of the antiviral response due disease can be explained by whom we how the adaptive immune response as to their ability to eliminate virally infect­ study and when we study them. Most cor­ well as innate immunity can be trained ed cells and produce antiviral cytokines relative clinical studies are undertaken to respond to pathogenic insults. Trained upon activation (17). NK cell function is in patients who are already hospitalized immunity refers to a more potent inflam­ heavily dependent on the cytokine milieu or critically ill because those are the ones matory response caused by long­lasting that these cells act on, and both IFNs and accessible for blood samples, while mild­ epigenetic modifications in myeloid pro­ other proinflammatory cytokines pro­ ly symptomatic or asymptomatic patients genitors (11). The lack of specificity of duced by trained myeloid cells can prime have not been properly studied because the secondary response may be the key to and boost NK antiviral functions. Viral they remain at home in self­quarantine. successfully exploiting trained immunity infections, particularly with cytomeg­ Murine studies, which are highly con­ against COVID-19 and future pandemics. alovirus, generate a subset of memory trolled, will therefore be very informative The bacille Calmette­Guérin (BCG, NK cells that respond more potently to a when contemplating when to therapeuti­
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