The many faces of the anti-COVID immune response

Santosha A Vardhana, Jedd D Wolchok, Santosha A Vardhana, Jedd D Wolchok

Abstract

The novel 2019 strain of coronavirus is a source of profound morbidity and mortality worldwide. Compared with recent viral outbreaks, COVID-19 infection has a relatively high mortality rate, the reasons for which are not entirely clear. Furthermore, treatment options for COVID-19 infection are currently limited. In this Perspective, we explore the contributions of the innate and adaptive immune systems to both viral control as well as toxicity during COVID-19 infections and offer suggestions to both understand and therapeutically modulate anti-COVID immunity.

Conflict of interest statement

Disclosures: S.A. Vardhana reported personal fees from Immunai and personal fees from ADC Therapeutics outside the submitted work; in addition, S.A. Vardhana had a patent to PCT/US19/27610 pending. J.D. Wolchok reported personal fees from Tizona Pharmaceuticals, Adaptive Biotechnologies, Imvaq, Beigene, and Linneaus; and grants from AstraZeneca, Bristol Myers Squibb, and Sephora outside the submitted work. In addition, J.D. Wolchok had a patent to alphavirus replicon particles expressing TRP2 issued, a patent to Newcastle disease viruses for cancer therapy issued, a patent to xenogeneic DNA vaccines with royalties paid "Merial," a patent to myeloid-derived suppressor cell (MDSC) assay with royalties paid "Serametrix," a patent to anti-PD1 antibody licensed "Agenus," a patent to anti-CTLA4 antibodies licensed "Agenus," a patent to anti-GITR antibodies and methods of use thereof licensed "Agenus/Incyte," a patent to genomic signature to identify responders to ipilimumab in melanoma pending, a patent to engineered vaccinia viruses for cancer immunotherapy pending, a patent to anti-CD40 agonist mAb fused to monophosphoryl lipid A (MPL) for cancer therapy pending, a patent to CAR+ T cells targeting differentiation antigens as means to treat cancer pending, a patent to identifying and treating subjects at risk for checkpoint blockade therapy associated colitis pending, a patent to immunosuppressive follicular helper-like T cells modulated by immune checkpoint blockade pending, and a patent to phosphatidylserine targeting agents and uses thereof for adoptive T-cell therapies pending. J.D. Wolchok is a paid consultant for: Adaptive Biotech, Amgen, Apricity, Ascentage Pharma, Astellas, AstraZeneca, Bayer, Beigene, Bristol Myers Squibb, Celgene, Chugai, Eli Lilly, Elucida, F Star, Imvaq, Janssen, Kyowa Hakko Kirin, Linneaus, Merck, Neon Therapuetics, Novaritis, Polynoma, Psioxus, Recepta, Takara Bio, Trieza, Truvax, Serametrix, Surface Oncology, Syndax, and Syntalogic.

© 2020 Vardhana and Wolchok.

Figures

Figure 1.
Figure 1.
Innate immune regulation of antiviral defense and tissue toxicity. Virally derived DAMPs and PAMPs activate tissue-resident macrophages. Downstream production of IL-6 and IL-1β recruit neutrophils and CD8+ T cells, which control viral growth (left) but also induce tissue damage, leading to alveolar flooding and fibrosis (right). MMP, matrix metalloproteases.
Figure 2.
Figure 2.
Distinctions between CAR-T and virally mediated hypercytokinemia.(A and B) During CAR-T cell–driven CRS (A), blockade of macrophage-derived IL-1 and IL-6 limits tissue toxicity without interfering with antitumor immunity. However, during viral infections (B), blockade of macrophage function may impair both innate and adaptive viral control.
Figure 3.
Figure 3.
Immune dysregulation during chronic viral infections.(A and B) During acute viral infections (A), early innate and adaptive immune function lead to viral suppression, followed by development of adaptive immunity. During chronic viral infections (B), persistent virus leads to T cell depletion and exhaustion while triggering ongoing innate immune inflammation. NK, natural killer.
Figure 4.
Figure 4.
Enhancing innate and adaptive immunity to combat COVID-19 infections.(A) Enhancing antiviral sensing through activation of type I interferon responses or adaptive immunity by rescuing T cells from exhaustion-dependent cell death may improve anti–COVID-19 immunity, particularly in the context of blocking macrophage-dependent cytokine production. (B) Distinct strategies for modulating innate and adaptive immune responses during early and late COVID-19 infection may lead to more effective viral control.

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