tetano
Editor, Senior Moderator
Virulence
. 2022 Oct 22.
doi: 10.1080/21505594.2022.2139474. Online ahead of print.
PA-X Protein of H1N1 Subtype Influenza Virus Disables the Nasal Mucosal Dendritic Cells for Strengthening Virulence
Tao Qin[SUP] 1 2 3 4 [/SUP], Yulian Chen[SUP] 1 [/SUP], Dandan Huangfu[SUP] 1 [/SUP], Yinyan Yin[SUP] 5 [/SUP], Xinyu Miao[SUP] 1 [/SUP], Yuncong Yin[SUP] 1 2 3 4 [/SUP], Sujuan Chen[SUP] 1 2 3 4 [/SUP], Daxin Peng[SUP] 1 2 3 4 [/SUP], Xiufan Liu[SUP] 1 2 3 [/SUP]
Affiliations
Abstract
PA-X protein arises from a ribosomal frameshift in the PA of influenza A virus (IAV). However, the immune regulatory effect of the PA-X protein of H1N1 viruses on the nasal mucosal system remains unclear. Here, a PA-X deficient H1N1 rPR8 viral strain (rPR8-△PAX) was generated and its pathogenicity was determined. The results showed that PA-X was a pro-virulence factor in mice. Furthermore, it reduced the ability of H1N1 viruses to infect dendritic cells (DCs), the regulator of the mucosal immune system, but not non-immune cells (DF-1 and Calu-3). Following intranasal infection of mice, CCL20, a chemokine that monitors the recruitment of submucosal DCs, was downregulated by PA-X, resulting in an inhibition of the recruitment of CD11b+ DCs to submucosa. It also attenuated the migration of CCR7+ DCs to cervical lymph nodes and inhibited DC maturation with low MHC II and CD40 expression. Moreover, PA-X suppressed the maturation of phenotypic markers (CD80, CD86, CD40, and MHC II) and the levels of secreted pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) while enhancing endocytosis and levels of anti-inflammatory IL-10 in vitro, suggesting an impaired maturation of DCs that the key step for the activation of downstream immune responses. These findings suggested the PA-X protein played a critical role in escaping the immune response of nasal mucosal DCs for increasing the virulence of H1N1 viruses.
Keywords: Dendritic cells; H1N1; Influenza A virus; Innate immunity; PA-X protein; Virulence.
. 2022 Oct 22.
doi: 10.1080/21505594.2022.2139474. Online ahead of print.
PA-X Protein of H1N1 Subtype Influenza Virus Disables the Nasal Mucosal Dendritic Cells for Strengthening Virulence
Tao Qin[SUP] 1 2 3 4 [/SUP], Yulian Chen[SUP] 1 [/SUP], Dandan Huangfu[SUP] 1 [/SUP], Yinyan Yin[SUP] 5 [/SUP], Xinyu Miao[SUP] 1 [/SUP], Yuncong Yin[SUP] 1 2 3 4 [/SUP], Sujuan Chen[SUP] 1 2 3 4 [/SUP], Daxin Peng[SUP] 1 2 3 4 [/SUP], Xiufan Liu[SUP] 1 2 3 [/SUP]
Affiliations
- PMID: 36271710
- DOI: 10.1080/21505594.2022.2139474
Abstract
PA-X protein arises from a ribosomal frameshift in the PA of influenza A virus (IAV). However, the immune regulatory effect of the PA-X protein of H1N1 viruses on the nasal mucosal system remains unclear. Here, a PA-X deficient H1N1 rPR8 viral strain (rPR8-△PAX) was generated and its pathogenicity was determined. The results showed that PA-X was a pro-virulence factor in mice. Furthermore, it reduced the ability of H1N1 viruses to infect dendritic cells (DCs), the regulator of the mucosal immune system, but not non-immune cells (DF-1 and Calu-3). Following intranasal infection of mice, CCL20, a chemokine that monitors the recruitment of submucosal DCs, was downregulated by PA-X, resulting in an inhibition of the recruitment of CD11b+ DCs to submucosa. It also attenuated the migration of CCR7+ DCs to cervical lymph nodes and inhibited DC maturation with low MHC II and CD40 expression. Moreover, PA-X suppressed the maturation of phenotypic markers (CD80, CD86, CD40, and MHC II) and the levels of secreted pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) while enhancing endocytosis and levels of anti-inflammatory IL-10 in vitro, suggesting an impaired maturation of DCs that the key step for the activation of downstream immune responses. These findings suggested the PA-X protein played a critical role in escaping the immune response of nasal mucosal DCs for increasing the virulence of H1N1 viruses.
Keywords: Dendritic cells; H1N1; Influenza A virus; Innate immunity; PA-X protein; Virulence.