DENV特异性IgA在DENV感染的抗体依赖性增强过程中发挥保护性和非病理性功能。

IF 6.7 1区 医学 Q1 Immunology and Microbiology
PLoS Pathogens Pub Date : 2023-08-28 eCollection Date: 2023-08-01 DOI:10.1371/journal.ppat.1011616
Adam D Wegman, Mitchell J Waldran, Lauren E Bahr, Joseph Q Lu, Kristen E Baxter, Stephen J Thomas, Adam T Waickman
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引用次数: 0

摘要

登革热是全球日益严重的公共卫生负担,每年约有1亿例有症状的病例和数万人死亡。先前感染一种血清型登革热病毒(DENV)是已知的在二次感染异源血清型后发生严重疾病的最大风险因素,随着血清型在流行地区的共同传播,这种风险会增加。这种疾病风险被认为是由原发感染期间产生的IgG同种型抗体介导的,该抗体很难中和异源DENV血清型,而是调理病毒粒子以供携带FcγR的细胞吸收。这种感染的抗体依赖性增强(ADE)导致更大比例的易感细胞感染、更高的病毒血症和更大的免疫病理学。我们之前已经描述了登革热感染期间血清IgA反应的诱导,以及典型的IgM和IgG反应,并表明DENV反应性IgA可以中和DENV并竞争性拮抗IgG介导的ADE。在这里,我们评估了IgA自身引起ADE的可能性。我们发现,在表达FcαR和FcγRs的细胞中,IgG而不是IgA介导感染的ADE。IgG介导的ADE刺激原代人类巨噬细胞产生显著更高的促炎细胞因子,而IgA不影响或轻微抑制这种产生。从机制上讲,我们发现DENV/IgG免疫复合物比DENV/IgA复合物或单独的病毒更有效地结合易感细胞。最后,我们发现,在原发性登革热感染过程中,FcγRI(CD64)的表达在急性病毒血症期间增加,而FcγRIIa(CD32)和FcαR(CD89)的表达减少,从而进一步限制了IgA在DENV存在下促进ADE的能力。总的来说,这些数据说明了IgA在登革热感染ADE期间的独特保护作用,并强调了DENV特异性IgA的潜在治疗和预后价值。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
DENV-specific IgA contributes protective and non-pathologic function during antibody-dependent enhancement of DENV infection.

Dengue represents a growing public health burden worldwide, accounting for approximately 100 million symptomatic cases and tens of thousands of fatalities yearly. Prior infection with one serotype of dengue virus (DENV) is the greatest known risk factor for severe disease upon secondary infection with a heterologous serotype, a risk which increases as serotypes co-circulate in endemic regions. This disease risk is thought to be mediated by IgG-isotype antibodies raised during a primary infection, which poorly neutralize heterologous DENV serotypes and instead opsonize virions for uptake by FcγR-bearing cells. This antibody-dependent enhancement (ADE) of infection leads to a larger proportion of susceptible cells infected, higher viremia and greater immunopathology. We have previously characterized the induction of a serum IgA response, along with the typical IgM and IgG responses, during dengue infection, and have shown that DENV-reactive IgA can neutralize DENV and competitively antagonize IgG-mediated ADE. Here, we evaluate the potential for IgA itself to cause ADE. We show that IgG, but not IgA, mediated ADE of infection in cells expressing both FcαR and FcγRs. IgG-mediated ADE stimulated significantly higher pro-inflammatory cytokine production by primary human macrophages, while IgA did not affect, or slightly suppressed, this production. Mechanistically, we show that DENV/IgG immune complexes bind susceptible cells significantly more efficiently than DENV/IgA complexes or virus alone. Finally, we show that over the course of primary dengue infection, the expression of FcγRI (CD64) increases during the period of acute viremia, while FcγRIIa (CD32) and FcαR (CD89) expression decreases, thereby further limiting the ability of IgA to facilitate ADE in the presence of DENV. Overall, these data illustrate the distinct protective role of IgA during ADE of dengue infection and highlight the potential therapeutic and prognostic value of DENV-specific IgA.

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来源期刊
PLoS Pathogens
PLoS Pathogens 生物-病毒学
CiteScore
11.40
自引率
3.00%
发文量
598
审稿时长
2 months
期刊介绍: Bacteria, fungi, parasites, prions and viruses cause a plethora of diseases that have important medical, agricultural, and economic consequences. Moreover, the study of microbes continues to provide novel insights into such fundamental processes as the molecular basis of cellular and organismal function.
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