Breakthrough infection evokes the nasopharyngeal innate immune responses established by SARS-CoV-2-inactivated vaccine

Front Immunol. 2023 Jun 29:14:1181121. doi: 10.3389/fimmu.2023.1181121. eCollection 2023.

Abstract

Nasopharyngeal immune responses are vital for defense against SARS-CoV-2 infection. Although vaccination via muscle immunization has shown a high efficacy in reducing severity and death in COVID-19 infection, breakthrough infection frequently happens because of mutant variants and incompletely established mucosal immunity, especially in the upper respiratory tract. Here, we performed a single-cell RNA and T-cell receptor repertoire sequencing and delineated a high-resolution transcriptome landscape of nasopharyngeal mucosal immune and epithelial cells in vaccinated persons with breakthrough infection and non-vaccinated persons with natural infection as control. The epithelial cells showed anti-virus gene expression diversity and potentially recruited innate immune cells into the nasopharyngeal mucous of vaccinated patients. Upon infection, they released significant pro-inflammatory cytokines and chemokines by macrophages and monocytes and expressed antigen-presenting relevant genes by dendritic cells. Such immune responses of nasopharyngeal innate immune cells would facilitate the strengthened expression of cytotoxic genes in virus-specific T-cell or B-cell differentiation into antibody-secreting cells at the early stage of breakthrough infection through cell interaction between innate and adaptive immune cells. Notably, these alterations of nasopharyngeal immune cells in breakthrough infection depended on the activated Nuclear factor-κB (NF-κB) and NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) signaling rather than type I interferon responses due to the general reduction in interferon-stimulated gene expression. Our findings suggest that vaccination potentially strengthens innate immune barriers and virus-specific memory immune cell responses, which could be quickly activated to defend against variant breakthrough infection and maintain nasopharyngeal epithelial cell integrity. Thus, this study highlights the necessity of a boost via nasal mucous after intramuscular immunization.

Keywords: SARS-CoV-2; breakthrough infection; innate immune memory; mucosal immunity; single-cell RNA sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breakthrough Infections
  • COVID-19 Vaccines*
  • COVID-19* / prevention & control
  • Humans
  • Immunity, Innate
  • SARS-CoV-2
  • Vaccines, Inactivated

Substances

  • COVID-19 Vaccines
  • Vaccines, Inactivated

Grants and funding

This work was supported, in part, by grants from the National Natural Science Foundation of China (81901616 to XH; 92169204 and 82025022 to ZZ); the National Science and Technology Major Project of the Etiology and Epidemic Prevention Technology System (2022YFC2304503); Guangdong Basic and Applied Basic Research Foundation (2023A1515010756 to XH); The Science and Technology General Program and Innovation Committee of Shenzhen Municipality (JCYJ20220530163409023 to XH; JSGG20220226085550001 to ZZ); The Shenzhen Science and Technology Program (ZDSYS20210623091810030 to ZZ); R&D Program of Guangzhou Laboratory (SRPG22-006 to ZZ); The Central Charity Fund of Chinese Academy of Medical Science (2020-PT310-009 to ZZ). The Science and Technology Innovation Committee of Shenzhen Municipality (JSGG20220606140200002 to XT).