chuka_lis (chuka_lis) wrote,
chuka_lis
chuka_lis

О реинфекциях и иммунитете

Любопытная статья бразильцев, о вкладе врожденного и приобретенного иммунитета в повторную заражаемость ковидом, на примере 2 пар однояйцовых близнецов.
Вкратце- 2 близнецов,  до 30 лет, одна из которых медработник, переболели ковидом в начале 2020 года (одна чуть раньше, вторая попозже). Подтвержденно тестами, и серологически, на подтипы антител, к разным антигенам коронавиурса (и других коронавирусов тоже), через полтора месяца после диагноза (май), с новым диагнозом, и далее, после выздоровления. Уровни всего были похожие. Однако, спустя 4 месяца после выздоровления, в конце июня, одна из близнецов (медработник) снова заболела, в этот раз - тяжело, с реанимацией в начале июля, причем уровни нейтрализующих антител к РСЧ коронавируса у нее были при поступлении в больницу в 2 раза выше, чем месяц спустя после 1 болезни. У сестер были все схожие данные по гуморальному иммунитету, и по врожденному иммунитету тоже (и по течению болезни в 1 раз), и отличались только реакции Т-лимфоцитов (которые, как и цитокины ( в августе), начали исследовать плотно только после 2 тяжелого случая, даже еще позже (октябрь).
По какой-то причине у заболевшей 2 раз тяжело, Т-хелперы и Т-киллеры, как бы "ослепли", и можно сказать, в упор почти не видели коронавируса (хотя интерферон и антитела при этом были "на уровне").Так что приобретнный клеточный иммунитет у переболевших ковидом близнецов может отличаться, и, вероятно, играть ключевую роль при последующей реинфекции (или быть результатом 2го ковида).
У не близнецов конечно, тоже, но на близнецах это четко видно. Вторая, не заболевшая ковидом, была как бы контролем, так же контролем была другая пара близнецов, со всеми сходными показателями, заразившихся 1 раз, и перенесших ковид легко. С другой стороны- не известно еще, заболеет ли ковидом сестра и как она будет болеть 2 раз, кстати. Кроме того, тк геном вируса не секвенировали, авторы не уверены, это реинфекция в чистом виде или "возвращение" того же самого вируса,хотя и склоняются к реинфекции, в силу ее работы и неизбежных частых контактов с ковидными..
Осталось выяснить- когда и почему ее Т-лимфоциты перестали распознавать презентованные эпитопы коронавируса.
Если дело только в этом, конечно. Ведь до и во время первой болезни клеточный иммунитет не исследовали. Да и  во время второй тоже. Однако, поскольку разница у близнецов только в этом, авторы полагают- что это и есть фактор, определяющий более тяжелое течение повторной инфекции.
Here we describe a comprehensive assessment of innate and adaptive immune response against SARS-CoV-2 in two pairs of monozygotic twins, including a case of severe COVID-19 recurrence in one of two twin, a health care worker. We found that the only immune parameter that was substantially lower in the COVID-19 recurrence case as compared to her twin sibling and a second pair of MZ twins was the breadth (number of recognized epitopes) of the CD4+ and CD8+ T cell responses. To our knowledge, this is the first report of innate and T cell immune responses in the context of COVID-19 recurrence and reinfection. Of note, there were also fluctuations in some other immune parameters within each MZ twin pair. Innate Type I/III IFN responses are the first line of cellular defense against RNA viruses. SARS-CoV-2 induces lower Type I/III IFN responses as compared to other respiratory viruses due to viral-encoded proteins that dampen such responses (4). An immune response characterized by a weak, delayed production of Type I/III interferons contributes to severe forms of the disease (17). The finding that all four tested patients including the COVID-19
recurrence case presented an early, strong type I/III IFN response indicates that recurrence was not associated with failure in the innate IFN response. Protection against reinfection by viruses is mainly mediated by adaptative immune responses. Memory responses to secondary exposure to pathogen limit or prevent reinfection (5). Immunological investigation of COVID-19 recurrence and reinfection has been so far limited to antibody reactivity profiles. In a recent review of 16 reinfection cases ocurring 19-142 days after the first infection episode, 10 reported anti-SARS-CoV-2IgG testing, 6 of which displayed positive serology at the time of second infection; reinfections occurred in patients with all degrees of severity in the primary infection, but 75% of the reinfections were asymptomatic or mild (5). Neutralizing antibodies (nAb) were detected at the time of reinfection in three case reports (3, 6, 7), while only one case reported reinfection in the absence of detectable nAb (8) suggesting that responses beyond neutralizing antibodies are important to control reinfection. In our study, reinfected case V01 presented nAb 6 weeks after COVID-19 recurrence. Although we cannot ensure that neutralizing antibodies were present earlier when recurrence occurred, increased levels of anti-SARS-CoV-2 IgG were detectable at hospital admission indicating that COVID-19 recurrence boosted IgG levels, which is in line with literature reports (5). Our finding that the CD4+ and CD8+ T cell responses of the COVID-19 recurrence case had a drastically reduced breadth 4 months after hospital discharge is indicative of a low SARS-CoV-2-specific T cell response. This is in contrast with the finding that hospitalized patients display a larger breadth of CD4+ T cell responses than outpatients (18). Given the importance of T cell responses associated with COVID-19 infection (19), a dampened CD4+ T cell response can have important consequences for many aspects of anti-SARS-COV-2 immunity. Asymptomatic and mild cases of CoVID-19 are correlated with specific CD4+ and CD8+ T cell responses, but not with IgG or neutralizing antibody, suggesting that T cells are the primary effectors controlling a primary SARS-CoV-2 infection (4, 20, 21). The dominant cytokine produced by virus-specific CD4+ T cells is IFNγ with a Th1 profile, associated with antiviral activity. CD4+ T cells protect mice from lethal SARS-CoV infection (22), and Th1 CD4+ T cells are important to provide help for the cytotoxic CD8+ T responses crucial for clearance of viral infections. CD4+ T follicular helper cells contribute for B cell responses, and IL-22-producing T cells observed in COVID-19 are key for maintenance of mucosal repair, particularly gut and lung epithelial cells (4). It is unlikely that the reduced T cell responses observed in V01 are due the absence of HLA presentation to T cells, since her MZ twin V02 carrying the same HLA alleles displayed a broad recognition profile. Also, it is not likely that the contrasting T cell responses observed between the two siblings is a result of previous exposure to cross-reacting viruses (23), since their IgG profile against human endemic coronaviruses’ RBD was nearly identical.
In short, our results suggest that the failure in inducing a broad T cell response might have enhanced susceptibility to COVID-19 recurrence in the reported case. Our data may support a prime role for T cells in protection against reinfection. Given the increased concern that SARS-CoV-2 variants escaping antibody neutralization could give rise to a massive raise in reinfection (24, 25), our case stresses the importance of T cell immune responses in protection against reinfection. This is in line with the reported lack of deleterious effect of virus variants in the cellular immune response (26). Further investigation in a larger cohort can shed light on whether T cell dysfunction is a common mechanism for recurrence of COVID-19.
Tags: иммунитет, коронавирус, статьи
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