Humoral signatures of protective and pathological SARS-CoV-2 infection in children

Bartsch, Yannic C.; Wang, Chuangqi; Zohar, Tomer; Fischinger, Stephanie; Atyeo, Caroline; Burke, John S.; Kang, Jaewon; Edlow, Andrea G.; Fasano, Alessio; Baden, Lindsey R.; Nilles, Eric J.; Woolley, Ann E.; Karlson, Elizabeth W.; Hopke, Alex; Irimia, Daniel; Fischer, Eric S.; Ryan, Edward T.; Charles, Richelle C.; Jülg, Boris; Lauffenburger, Douglas A.; Yonker, Lael M.; Alter, Galit

doi:10.1038/s41591-021-01263-3

Cited by 142 publications

(167 citation statements)

References 49 publications

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“…In consideration of the core pathological roles by aberrantly expanded macrophages in the severe cases ( 20 ) as well as in the post-recovery cardiovascular ( 21 ) and autoimmune pathologies of COVID19 (i.e. Multisystem Inflammatory Syndrome in Children [MIS-C]) ( 22, 23 ), future investigations on the treatment potential of C010DS-Zn against such macrophage-mediated inflammatory pathologies as those seen in macrophage activation syndrome (MAS), severe COVID19, post-COVID19 myocardial damage ( 21 ), and MIS-C ( 23 ) are warranted.…”

Section: Discussionmentioning

confidence: 99%

Parthanatos-inducing zinc agent C010DS-Zn elicits anti-tumor immune responses involving T cells and macrophages in vivo

Chung¹,

Z²,

Wm³

et al. 2021

Preprint

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Immune checkpoint inhibitors opened a new horizon in cancer therapy by enabling durable and complete responses in patients, but their wider application against general solid cancers has been hampered by the lack of a broadly acting anti-cancer immune response initiating agents. Parthanatos is a previously unexplored immunogenic programmed necrosis mechanism that is triggered by the hyperactivation of PARP DNA repair and executed by an efficient DNA-fragmentation mechanism. We developed a proprietary macromolecular zinc complex agent C010DS-Zn that efficiently induced parthanatos against 4T1 murine cancer cells in vitro, which was characterized as PARP-mediated necrotic death with massive DNA damages. Ex vivo screening of its cytotoxicity against a panel of 53 low-passage human solid cancer PDX tumor fragments demonstrated its consistent delivery of characteristically DNA-damaging cell death that was unseen in the corresponding apoptosis positive controls. Further characterization of its in vivo treatment effects versus the immunosuppressive 4T1-Balb/c and immunogenic CT26-Balb/c syngeneic cancer models showed that sufficiently high intravenous C010DS-Zn treatments led to robust initiation of the tumor-suppressed antitumor immune compartments such as T cells and macrophages. At lower non-anticancer doses, C010DS-Zn treatment still led to significantly reduced macrophage content and inflammation in the 4T1 tumor, suggesting its potential utility against macrophage-mediated inflammations such as those seen in MIS-C or COVID19. Given the observation of its low serum bioavailability in a rat pharmacokinetic study, these results suggest potential development opportunities for C010DS-Zn to become a widely applicable immune initiation agent with chemo-like broad applicability upon its pharmacokinetic improvements.

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Section: Discussionmentioning

confidence: 99%

Parthanatos-inducing zinc agent C010DS-Zn elicits anti-tumor immune responses involving T cells and macrophages in vivo

Chung¹,

Z²,

Wm³

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…This may correspond with higher neutralising antibodies, but higher IgG and IgA levels may also perpetuate innate cell activity, primarily in neutrophils expressing surface Fc receptors. 26 Early phase rise in IgM levels was seen in asymptomatic, mild and severe cases. 16 Early phase rise in IgM, persistent IgG and waning IgA levels were observed in paediatric COVID-19.…”

Section: Childhood and Adult Immune Responses To Sars-cov-2mentioning

confidence: 98%

“… 27 Children with PIMS-TS maintained high IgG levels with enduring Fc receptor-binding capacity which were capable of monocyte activation and sustained hyperinflammatory activity. 26 …”

Section: Childhood and Adult Immune Responses To Sars-cov-2mentioning

confidence: 99%

Understanding COVID-19: are children the key?

Warner

Richter

Stamataki

et al. 2021

bmjpo

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The devastating impact of the COVID-19 pandemic on global health and economic stability is immeasurable. The situation is dynamic and fast-evolving, with the world facing new variants of concern which may have immune escape potential. With threatened treatment and preventative strategies at stake, and the prospect of reinfection prolonging the pandemic, it is more crucial than ever to understand the pathogenesis of SARS-CoV-2 infection, which intriguingly disproportionately affects adults and the elderly. Children infected with SARS-CoV-2 remain largely asymptomatic or undergo a transient mild illness. Understanding why children have a milder phenotype and a significant survival advantage may help identify modifiable risk factors in adults. Current evidence suggests adults with COVID-19 show variability in innate and adaptive immune responses, which result in uncontrolled proinflammatory cytokine production in some patients, leading to severe disease and mortality. Children with acute COVID-19 infection seldom progress to acute respiratory distress syndrome and are less likely to exhibit the cytokine storm which is so prominent in adults. Even with the Kawasaki-like illness, a hyperinflammation syndrome also known as paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2, mortality is low. The key to successfully combating SARS-CoV-2 and future zoonotic pandemics may lie in understanding these critical differences and merits focused consideration and research. The impact of community transmission among asymptomatic children is unknown; sustained global decline in infection rates and control of the COVID-19 pandemic may not be achieved until vaccination of children occurs. In this review, we discuss the fundamental differences in the immune response between children and adults in the fight against SARS-CoV-2.

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“…Severe disease may be associated with a delay of the humoral response [88]. Children with multisystem inflammatory syndrome amount stronger antibody responses akin to more severely ill adults, and in contrast to either children or adults with mild illness [89].…”

Section: Immunogens and Humoral Immunitymentioning

confidence: 99%

“…T cell immunity arises, as anticipated, during infection, and the quality and quantity of the same varies according to the intensity of disease. [31,48,51,63,65,67,68,70,74,89,91,93,94,98,102,[109][110][111].…”

Section: Correlations With Immunity or Protectionmentioning

confidence: 99%

Passive Immunity Should and Will Work for COVID-19 for Some Patients

Cimolai¹

2021

CHI

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In the absence of effective antiviral chemotherapy and still in the context of emerging vaccines for severe acute respiratory syndrome-CoV-2 infections, passive immunotherapy remains a key treatment and possible prevention strategy. What might initially be conceived as a simplified donor-recipient process, the intricacies of donor plasma, IV immunoglobulins, and monoclonal antibody modality applications are becoming more apparent. Key targets of such treatment have largely focused on virus neutralization and the specific viral components of the attachment Spike protein and its constituents (e.g., receptor binding domain, N-terminal domain). The cumulative laboratory and clinical experience suggests that beneficial protective and treatment outcomes are possible. Both a dose-and a time-dependency emerge. Lesser understood are the concepts of bioavailability and distribution. Apart from direct antigen binding from protective immunoglobulins, antibody effector functions have potential roles in outcome. In attempting to mimic the natural but variable response to infection or vaccination, a strong functional polyclonal approach attracts the potential benefits of attacking antigen diversity, high antibody avidity, antibody persistence, and protection against escape viral mutation. The availability and ease of administration for any passive immunotherapy product must be considered in the current climate of need. There is never a perfect product, but yet there is considerable room for improving patient outcomes. Given the variability of human genetics, immunity, and disease, and given the nuances of the virus and its potential for change, passive immunotherapy can be developed that will be effective for some but not all patients. An understanding of such patient variability and limitations is just as important as the understanding of the direct interactions between immunotherapy and virus.

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Humoral signatures of protective and pathological SARS-CoV-2 infection in children

Cited by 142 publications

References 49 publications

Parthanatos-inducing zinc agent C010DS-Zn elicits anti-tumor immune responses involving T cells and macrophages in vivo

Parthanatos-inducing zinc agent C010DS-Zn elicits anti-tumor immune responses involving T cells and macrophages in vivo

Understanding COVID-19: are children the key?

Passive Immunity Should and Will Work for COVID-19 for Some Patients

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