Browsing by Author "Li, Chaofan"

Now showing 1 - 7 of 7
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    BCL6 modulates tissue neutrophil survival and exacerbates pulmonary inflammation following influenza virus infection
    (National Academy of Sciences, 2019-06-11) Zhu, Bibo; Zhang, Ruixuan; Li, Chaofan; Jiang, Li; Xiang, Min; Ye, Zhenqing; Kita, Hirohito; Melnick, Ari M.; Dent, Alexander L.; Sun, Jie; Pediatrics, School of Medicine
    Neutrophils are vital for antimicrobial defense; however, their role during viral infection is less clear. Furthermore, the molecular regulation of neutrophil fate and function at the viral infected sites is largely elusive. Here we report that BCL6 deficiency in myeloid cells exhibited drastically enhanced host resistance to severe influenza A virus (IAV) infection. In contrast to the notion that BCL6 functions to suppress innate inflammation, we find that myeloid BCL6 deficiency diminished lung inflammation without affecting viral loads. Using a series of Cre-transgenic, reporter, and knockout mouse lines, we demonstrate that BCL6 deficiency in neutrophils, but not in monocytes or lung macrophages, attenuated host inflammation and morbidity following IAV infection. Mechanistically, BCL6 bound to the neutrophil gene loci involved in cellular apoptosis in cells specifically at the site of infection. As such, BCL6 disruption resulted in increased expression of apoptotic genes in neutrophils in the respiratory tract, but not in the circulation or bone marrow. Consequently, BCL6 deficiency promoted tissue neutrophil apoptosis. Partial neutrophil depletion led to diminished pulmonary inflammation and decreased host morbidity. Our results reveal a previously unappreciated role of BCL6 in modulating neutrophil apoptosis at the site of infection for the regulation of host disease development following viral infection. Furthermore, our studies indicate that tissue-specific regulation of neutrophil survival modulates host inflammation and tissue immunopathology during acute respiratory viral infection.
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    Inhibition of the mitochondrial pyruvate carrier simultaneously mitigates hyperinflammation and hyperglycemia in COVID-19
    (American Association for the Advancement of Science, 2023) Zhu, Bibo; Wei, Xiaoqin; Narasimhan, Harish; Qian, Wei; Zhang, Ruixuan; Cheon, In Su; Wu, Yue; Li, Chaofan; Jones, Russell G.; Kaplan, Mark H.; Vassallo, Robert A.; Braciale, Thomas J.; Somerville, Lindsay; Colca, Jerry R.; Pandey, Akhilesh; Jackson, Patrick E. H.; Mann, Barbara J.; Krawczyk, Connie M.; Sturek, Jeffrey M.; Sun, Jie; Microbiology and Immunology, School of Medicine
    The relationship between diabetes and coronavirus disease 2019 (COVID-19) is bidirectional: Although individuals with diabetes and high blood glucose (hyperglycemia) are predisposed to severe COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can also cause hyperglycemia and exacerbate underlying metabolic syndrome. Therefore, interventions capable of breaking the network of SARS-CoV-2 infection, hyperglycemia, and hyperinflammation, all factors that drive COVID-19 pathophysiology, are urgently needed. Here, we show that genetic ablation or pharmacological inhibition of mitochondrial pyruvate carrier (MPC) attenuates severe disease after influenza or SARS-CoV-2 pneumonia. MPC inhibition using a second-generation insulin sensitizer, MSDC-0602K (MSDC), dampened pulmonary inflammation and promoted lung recovery while concurrently reducing blood glucose levels and hyperlipidemia after viral pneumonia in obese mice. Mechanistically, MPC inhibition enhanced mitochondrial fitness and destabilized hypoxia-inducible factor-1α, leading to dampened virus-induced inflammatory responses in both murine and human lung macrophages. We further showed that MSDC enhanced responses to nirmatrelvir (the antiviral component of Paxlovid) to provide high levels of protection against severe host disease development after SARS-CoV-2 infection and suppressed cellular inflammation in human COVID-19 lung autopsies, demonstrating its translational potential for treating severe COVID-19. Collectively, we uncover a metabolic pathway that simultaneously modulates pulmonary inflammation, tissue recovery, and host metabolic health, presenting a synergistic therapeutic strategy to treat severe COVID-19, particularly in patients with underlying metabolic disease.
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    PD-1hi CD8+ resident memory T cells balance immunity and fibrotic sequelae
    (Science Immunology, 2019-06-14) Wang, Zheng; Wang, Shaohua; Goplen, Nick P.; Li, Chaofan; Cheon, In Su; Dai, Qigang; Huang, Su; Shan, Jinjun; Ma, Chaoyu; Ye, Zhenqing; Xiang, Min; Limper, Andrew H.; Porquera, Eva-Carmona; Kohlmeier, Jacob E.; Kaplan, Mark H.; Zhang, Nu; Johnson, Aaron J.; Vassallo, Robert; Sun, Jie; Microbiology and Immunology, School of Medicine
    CD8+ tissue-resident memory T (TRM) cells provide frontline immunity in mucosal tissues. The mechanisms regulating CD8+ TRM maintenance, heterogeneity, and protective and pathological functions are largely elusive. Here, we identify a population of CD8+ TRM cells that is maintained by major histocompatibility complex class I (MHC-I) signaling, and CD80 and CD86 costimulation after acute influenza infection. These TRM cells have both exhausted-like phenotypes and memory features and provide heterologous immunity against secondary infection. PD-L1 blockade after the resolution of primary infection promotes the rejuvenation of these exhausted-like TRM cells, restoring protective immunity at the cost of promoting postinfection inflammatory and fibrotic sequelae. Thus, PD-1 serves to limit the pathogenic capacity of exhausted-like TRM cells at the memory phase. Our data indicate that TRM cell exhaustion is the result of a tissue-specific cellular adaptation that balances fibrotic sequelae with protective immunity.
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    Respiratory mucosal immunity against SARS-CoV-2 after mRNA vaccination
    (American Association for the Advancement of Science, 2022) Tang, Jinyi; Zeng, Cong; Cox, Thomas M.; Li, Chaofan; Son, Young Min; Cheon, In Su; Wu, Yue; Behl, Supriya; Taylor, Justin J.; Chakraborty, Rana; Johnson, Aaron J.; Schiavo, Dante N.; Utz, James P.; Reisenauer, Janani S.; Midthun, David E.; Mullon, John J.; Edell, Eric S.; Alameh, Mohamad G.; Borish, Larry; Teague, William G.; Kaplan, Mark H.; Weissman, Drew; Kern, Ryan; Hu, Haitao; Vassallo, Robert; Liu, Shan-Lu; Sun, Jie; Microbiology and Immunology, School of Medicine
    SARS-CoV-2 mRNA vaccination induces robust humoral and cellular immunity in the circulation; however, it is currently unknown whether it elicits effective immune responses in the respiratory tract, particularly against variants of concern (VOCs), including Omicron. We compared the SARS-CoV-2 S-specific total and neutralizing antibody responses, and B and T cell immunity, in the bronchoalveolar lavage fluid (BAL) and blood of COVID-19-vaccinated individuals and hospitalized patients. Vaccinated individuals had significantly lower levels of neutralizing antibody against D614G, Delta (B.1.617.2), and Omicron BA.1.1 in the BAL compared with COVID-19 convalescents despite robust S-specific antibody responses in the blood. Furthermore, mRNA vaccination induced circulating S-specific B and T cell immunity, but in contrast to COVID-19 convalescents, these responses were absent in the BAL of vaccinated individuals. Using a mouse immunization model, we demonstrated that systemic mRNA vaccination alone induced weak respiratory mucosal neutralizing antibody responses, especially against SARS-CoV-2 Omicron BA.1.1 in mice; however, a combination of systemic mRNA vaccination plus mucosal adenovirus-S immunization induced strong neutralizing antibody responses not only against the ancestral virus but also the Omicron BA.1.1 variant. Together, our study supports the contention that the current COVID-19 vaccines are highly effective against severe disease development, likely through recruiting circulating B and T cell responses during reinfection, but offer limited protection against breakthrough infection, especially by the Omicron sublineage. Hence, mucosal booster vaccination is needed to establish robust sterilizing immunity in the respiratory tract against SARS-CoV-2, including infection by the Omicron sublineage and future VOCs.
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    Tissue-resident CD4+ T helper cells assist the development of protective respiratory B and CD8+ T cell memory responses
    (American Association for the Advancement of Science, 2021) Son, Young Min; Cheon, In Su; Wu, Yue; Li, Chaofan; Wang, Zheng; Gao, Xiaochen; Chen, Yao; Takahashi, Yoshimasa; Fu, Yang-Xin; Dent, Alexander L.; Kaplan, Mark H.; Taylor, Justin J.; Cui, Weiguo; Sun, Jie; Microbiology and Immunology, School of Medicine
    Much remains unknown about the roles of CD4+ T helper cells in shaping localized memory B cell and CD8+ T cell immunity in the mucosal tissues. Here, we report that lung T helper cells provide local assistance for the optimal development of tissue-resident memory B and CD8+ T cells after the resolution of primary influenza virus infection. We have identified a population of T cells in the lung that exhibit characteristics of both follicular T helper and TRM cells, and we have termed these cells as resident helper T (TRH) cells. Optimal TRH cell formation was dependent on transcription factors involved in T follicular helper and resident memory T cell development including BCL6 and Bhlhe40. We show that TRH cells deliver local help to CD8+ T cells through IL-21-dependent mechanisms. Our data have uncovered the presence of a tissue-resident helper T cell population in the lung that plays a critical role in promoting the development of protective B cell and CD8+ T cell responses.
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    The Transcription Factor Bhlhe40 Programs Mitochondrial Regulation of Resident CD8+ T Cell Fitness and Functionality
    (Elsevier, 2019-09-17) Li, Chaofan; Zhu, Bibo; Son, Young Min; Wang, Zheng; Jiang, Li; Xiang, Min; Ye, Zhenqing; Beckermann, Kathryn E.; Wu, Yue; Jenkins, James W.; Siska, Peter J.; Vincent, Benjamin G.; Prakash, Y. S.; Peikert, Tobias; Edelson, Brian T.; Taneja, Reshma; Kaplan, Mark H.; Rathmell, Jeffrey C.; Dong, Haidong; Hitosugi, Taro; Sun, Jie; Microbiology and Immunology, School of Medicine
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    Uncoupling of macrophage inflammation from self-renewal modulates host recovery from respiratory viral infection
    (Cell Press, 2021) Zhu, Bibo; Wu, Yue; Huang, Su; Zhang, Ruixuan; Son, Young Min; Li, Chaofan; Cheon, In Su; Gao, Xiaochen; Wang, Min; Chen, Yao; Zhou, Xian; Nguyen, Quynh; Phan, Anthony T.; Behl, Supriya; Taketo, M. Mark; Mack, Matthias; Shapiro, Virginia S.; Zeng, Hu; Ebihara, Hideki; Mullon, John J.; Edell, Eric S.; Reisenauer, Janani S.; Demirel, Nadir; Kern, Ryan M.; Chakraborty, Rana; Cui, Weiguo; Kaplan, Mark H.; Zhou, Xiaobo; Goldrath, Ananda W.; Sun, Jie; Microbiology and Immunology, School of Medicine
    Tissue macrophages self-renew during homeostasis and produce inflammatory mediators upon microbial infection. We examined the relationship between proliferative and inflammatory properties of tissue macrophages by defining the impact of the Wnt/β-catenin pathway, a central regulator of self-renewal, in alveolar macrophages (AMs). Activation of β-catenin by Wnt ligand inhibited AM proliferation and stemness, but promoted inflammatory activity. In a murine influenza viral pneumonia model, β-catenin-mediated AM inflammatory activity promoted acute host morbidity; in contrast, AM proliferation enabled repopulation of reparative AMs and tissue recovery following viral clearance. Mechanistically, Wnt treatment promoted β-catenin-HIF-1α interaction and glycolysis-dependent inflammation while suppressing mitochondrial metabolism and thereby, AM proliferation. Differential HIF-1α activities distinguished proliferative and inflammatory AMs in vivo. This β-catenin-HIF-1α axis was conserved in human AMs and enhanced HIF-1α expression associated with macrophage inflammation in COVID-19 patients. Thus, inflammatory and reparative activities of lung macrophages are regulated by β-catenin-HIF-1α signaling, with implications for the treatment of severe respiratory diseases.