scholarly journals The orthopoxvirus type I IFN binding protein is essential for virulence and an effective target for vaccination

2008 ◽  
Vol 205 (4) ◽  
pp. 981-992 ◽  
Author(s):  
Ren-Huan Xu ◽  
Matthew Cohen ◽  
Yong Tang ◽  
Eric Lazear ◽  
J. Charles Whitbeck ◽  
...  
Keyword(s):  
Immune Response ◽  
Neutralizing Antibodies ◽  
Traditional Approach ◽  
Binding Protein ◽  
Type I ◽  
Type I Ifn ◽  
Type I Ifns ◽  
Recombinant Type ◽  
Natural Target

Nonliving antiviral vaccines traditionally target proteins expressed at the surface of the virion with the hope of inducing neutralizing antibodies. Orthopoxviruses (OPVs), such as the human smallpox virus and the mouse-equivalent ectromelia virus (ECTV; an agent of mousepox), encode immune response modifiers (IRMs) that can increase virulence by decreasing the host immune response. We show that one of these IRMs, the type I interferon (IFN) binding protein (bp) of ECTV, is essential for ECTV virulence and is a natural target of the antibody response. More strikingly, we demonstrate that immunization with recombinant type I IFN bp protects mice from lethal mousepox. Collectively, our experiments have important implications for our understanding of the role of IRMs in OPV virulence and of type I IFNs in OPV infections. Furthermore, our work provides proof of concept that effective antiviral vaccines can be made to prevent disease by targeting virulence factors as an alternative to the traditional approach that attempts to prevent infection by virus neutralization.

scholarly journals Antibodies against type-I Interferon: detection and association with severe clinical outcome in COVID-19 patients

2021 ◽  
Author(s):  
David Goncalves ◽  
Mehdi Mezidi ◽  
Paul Bastard ◽  
Magali Perret ◽  
Kahina Saker ◽  
...  
Keyword(s):  
Clinical Characteristics ◽  
Type I Interferon ◽  
Clinical Course ◽  
University Hospital ◽  
Type I ◽  
Type I Ifn ◽  
Type I Ifns ◽  
Recombinant Type ◽  
Circulating Autoantibodies

Objectives Impairment of type I interferon (IFN-I) immunity has been reported in critically ill COVID-19 patients. This defect can be explained by the presence of circulating autoantibodies against IFN-I. We set out to improve the detection and the quantification of such antibodies (Abs) in a cohort of severe Covid-19 patients, in an effort to better document the prevalence of these Abs as the pandemics evolves and how they correlate with the clinical course of the disease. Methods Anti-IFN-a Abs was investigated 84 critical COVID-19 patients who were admitted to ICU at the Lyon University Hospital, France with a commercially available kit (Thermo-Fisher). Results Twenty-one patients out of 84 (25%) had anti-IFNa2 Ab above cut-off (>34ng/mL) in sera. A neutralizing activity against IFN-a2 was evidenced in 15 of them, suggesting that 18% of patients were positive for neutralizing anti-IFN-a and -w auto-Abs. In addition, in most of patients with neutralizing IFN-I Abs, we noticed an impairment of the IFN-I response. However, we did not find any difference in terms of clinical characteristics or outcome between critical COVID-19 patients with or without neutralizing anti-IFN-a2 auto-Abs in these conditions. Finally, we detected anti-type I IFN auto-Abs in sera of COVID-19 patients were detected throughout the ICU stay. Conclusions We report that 18% of severe COVID-19 patients were positive for these Anti-Type-I IFN Abs, confirming the detrimental role of these Abs on the antiviral response. Our results further support the use of recombinant type I IFNs not targeted by the auto-Abs (e.g., IFN-b) in COVID-19 patients with an impaired IFN-I response.

Plasmacytoid Dendritic Cells (PDC) and Th17 Immune Response Contribution in Gut Acute Graft-Versus-Host-Disease (GVHD)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2968-2968
Author(s):  
Florent Malard ◽  
Céline Bossard ◽  
Jessy Arbez ◽  
Patrice Chevallier ◽  
Thierry Guillaume ◽  
...  
Keyword(s):  
Immune Response ◽  
Stem Cell ◽  
Autoimmune Diseases ◽  
Intestinal Mucosa ◽  
Th17 Cells ◽  
Acute Gvhd ◽  
Type I ◽  
Type I Ifn ◽  
Th17 Response

Abstract Abstract 2968 Background. Acute GVHD after allogeneic stem cell transplantation (allo-SCT) is an exaggerated immune response against alloantigens involving dysregulation of inflammatory cytokine cascades. Previous studies established an important role of Th1 cells in acute GVHD pathophysiology. However, the identification of proinflammatory Th17 cells which contribute to autoimmune diseases pathophysiology, raised the issue of the role of Th17 cells in human acute GVHD. Indeed, the contribution of Th17 cells in acute GVHD was assessed in GVHD mouse models with conflicting results. In addition, the role of the PDC subset (the professional type I IFN-secreting cells), which play an important role in triggering Th17-related cytokines and autoimmune diseases, is not yet established in the acute GVHD setting. This report investigated the role of Th17 cells and their interaction with PDC in gastrointestinal (GI) biopsies taken from patients with or without acute GVHD. Patients and Methods. Studies described in this report were performed in a single centre series of 21 patients who underwent allo-SCT for different hematological malignancies (n=19) and severe aplastic anemia (n=2). The median age of patients was 53 years (range, 16–69). The stem cell source was PBSCs in 19 cases (85%), CB in 2 cases and BM in one case. Ten patients received transplant from a matched-related donor, and 11 patients from a matched-unrelated donor. A reduced-intensity conditioning regimen was used in the majority of cases (n=19; 90%) Immunohistochemistry was performed on deparaffinized tissues sections using an indirect immunoperoxydase method. A quantitative evaluation of antigens expression was performed by counting the number of positive cells in the whole biopsy at 200 magnifications for each sample. Results. In this cohort, based on standard pathology criteria, 16 patients had a histologically proven gastrointestinal acute GVHD. In all cases, biopsies were taken before initiation of systemic corticosteroid therapy. The remaining 5 patients did not have histological signs of acute GVHD (and did not develop clinical signs of acute GVHD) and thus, were used as controls. In order to identify the Th17 cell population, biopsies were tested for expression of the CD161 and CCR6 markers, and ROR-gamma-t, the key transcription factor that orchestrates the differentiation of Th17 cells. Significantly higher numbers of ROR-gamma-t+ and CD161+ cells were counted in the intestinal mucosa of patients with acute GVHD compared with intestinal mucosa of patients without acute GVHD, mainly found in the lamina propria but also in the epithelium of altered glands (p=0.016 and p=0.009 for ROR-gamma-t and CD161 expression respectively). Given the role of PDCs in triggering Th17-related cytokines, we sought next to determine the proportion of PDCs in intestinal biopsies from these same patients. This analysis showed a significant increase of CD123+ PDCs in the intestinal mucosa of patients with acute GVHD compared with mucosa of patients without acute GVHD (p=0.017). Moreover, we observed a significant correlation between the number of CD123+ PDCs and ROR-gamma-t or CD161 expressing cells in the intestinal mucosa of acute GVHD patients, highlighting the link between PDC and Th17 cells. Conclusion. The current study shed some light on the role of Th17 cells in the context of gastro-intestinal acute GVHD. Using well-established specific markers, we show that Th17 cells infiltrate intestinal biopsies from patients with acute GVHD. In addition, Th17 infiltration was paralleled by the infiltration of PDCs, suggesting a potential new pathophysiological link between PDCs and Th17 response in the context of gastro-intestinal acute GVHD. This is consistent with studies showing that PDCs can drive the differentiation of Th17 cells. Functional analyses are currently ongoing. Although the exact mechanism that links type I IFN production to PDC-mediated Th17 responses is still unclear in acute GVHD, these data raise the prospect of future innovative approaches to optimize immunosuppression regimens for the treatment or prophylaxis of acute GVHD by targeting PDCs and the Th17 response. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Inhibition of Type I Interferon Signaling Abrogates Early Mycobacterium bovis Infection

2019 ◽  
Author(s):  
Jie Wang ◽  
Tariq Hussain ◽  
Kai Zhang ◽  
Yi Liao ◽  
Jiao Yao ◽  
...  
Keyword(s):  
Mycobacterium Bovis ◽  
Defense Mechanism ◽  
Histopathological Examination ◽  
Bacterial Count ◽  
Type I ◽  
Type I Ifn ◽  
Regulatory Pathways ◽  
Type I Ifns

Abstract Background: Mycobacterium bovis (M. bovis) is the principal causative agent of bovine tuberculosis; however, it may also cause serious infection in human being. Type I IFN is a key factor in reducing viral multiplication and modulating host immune response against viral infection. However, the regulatory pathways of Type I IFN signaling during M. bovis infection are not yet fully explored. Here, we investigate the role of Type I IFN signaling in the pathogenesis of M. bovis infection in mice. Methods: C57BL/6 mice were treated with IFNAR1-blocking antibody or Isotype control 24 hour before M. bovis infection. After 21 and 84 days of infection, mice were sacrificed and role of Type I IFN signaling in the pathogenesis of M. bovis was investigated. ELISA and qRT-PCR was performed to detect the expression of Type I IFNs and related genes. M. bovis induced lung lesions were assessed by histopathological examination and viable bacterial count was determined by CFU assay. Results: We observed an abundant expression of Type I IFNs in the serum and lung tissues of M. bovis infected mice. In vivo blockade of Type I IFN signaling reduced the recruitment of neutrophils to the lung tissue, mediated the activation of macrophages leading to an increased pro-inflammatory profile and regulated the inflammatory cytokine production. However, no impact was observed on T cell recruitment and activation in the early acute phase of infection. Additionally, blocking of type I IFN signaling reduced bacterial burden in the infected mice as compared to untreated infected mice. Conclusions: Altogether, our results reveal that Type I IFN mediates a balance between M. bovis-mediated inflammatory reaction and host defense mechanism. Thus, modulating Type I IFN signaling could be exploited as a therapeutic strategy against a large repertoire of inflammatory disorders including tuberculosis.

Plasmacytoid Dendritic Cells (PDC) and Th17 Immune Response Contribution in Skin Acute Graft-Versus-Host-Disease (GVHD)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4103-4103
Author(s):  
Florent Malard ◽  
Céline Bossard ◽  
Patrice Chevallier ◽  
Thierry Guillaume ◽  
Jacques Delaunay ◽  
...  
Keyword(s):  
Immune Response ◽  
Stem Cell ◽  
Autoimmune Diseases ◽  
Th17 Cells ◽  
Acute Gvhd ◽  
Unrelated Donor ◽  
Type I ◽  
Type I Ifn ◽  
Th17 Response

Abstract Abstract 4103 Background. Acute GVHD after allogeneic stem cell transplantation (allo-SCT) is an exaggerated immune response against alloantigens involving dysregulation of inflammatory cytokine cascades. Previous studies established an important role of Th1 cells in acute GVHD pathophysiology. However, the identification of proinflammatory Th17 cells which contribute to autoimmune diseases pathophysiology, raised the issue of the role of Th17 cells in human acute GVHD. Indeed, the contribution of Th17 cells in acute GVHD was assessed in GVHD mouse models with conflicting results. In addition, the role of the PDC subset (the professional type I IFN-secreting cells), which play an important role in triggering Th17-related cytokines and autoimmune diseases, is not yet established in the acute GVHD setting. This report investigated the role of Th17 cells and their interaction with PDC in cutaneous biopsies taken from patients with or without acute GVHD. Patients and Methods. Studies described in this report were performed in a single centre series of 38 patients who underwent allo-SCT for different hematological malignancies (n=37) and severe aplastic anemia (n=1). The median age of patients was 52 years (range, 17–70). The stem cell source was PBSCs in 27 cases (71%), CB in 6 cases and BM in 5 cases. 11 patients received transplant from a matched-related donor, and 27 patients from an unrelated donor. A reduced-intensity conditioning regimen was used in the majority of cases (n=29; 76%) Immunohistochemistry was performed on deparaffinized tissues sections using an indirect immunoperoxydase method. A quantitative evaluation of antigens expression was performed by counting the number of positive cells in the whole biopsy at 200 magnifications for each sample. Results. In this cohort, based on standard pathology criteria, 29 patients had a histologically proven skin acute GVHD. In all cases, biopsies were taken before initiation of systemic corticosteroid therapy. The remaining 9 patients did not have histological signs of acute GVHD (and did not develop clinical signs of acute GVHD) and thus, were used as controls. In order to identify the Th17 cell population, biopsies were tested for expression of the CD161 and CCR6 markers, and ROR-gamma-t, the key transcription factor that orchestrates the differentiation of Th17 cells. Significantly higher numbers of ROR-gamma-t+, CD161+ and CCR6+ cells were counted in the skin of patients with acute GVHD compared with intestinal mucosa of patients without acute GVHD, mainly found in the lamina propria but also in the epithelium of altered glands (p=0.001, p<0.0001 and p=0.01 for ROR-gamma-t, CD161 and CCR6 expression respectively).Given the role of PDCs in triggering Th17-related cytokines, we sought next to determine the proportion of PDCs in cutaneous biopsies from these same patients. This analysis showed a significant increase of BDCA2+ PDCs in the skin of patients with acute GVHD compared with skin of patients without acute GVHD (p=0.03). Moreover, we observed a strong expression of the type I IFN-inducible protein Mx1 in the skin of patients with acute GVHD compared with skin of patients without acute GVHD, reflecting the high production of type I IFN by the BDCA2+ PDCs. Conclusion. The current study shed some light on the role of Th17 cells in the context of cutaneous acute GVHD. Using well-established specific markers, we show that Th17 cells infiltrate skin biopsies from patients with acute GVHD. In addition, Th17 infiltration was paralleled by the infiltration of PDCs, suggesting a potential new pathophysiological link between PDCs and Th17 response in the context of cutaneous acute GVHD. This is consistent with studies showing that PDCs can drive the differentiation of Th17 cells. Functional analyses are currently ongoing. These data raise the prospect of future innovative approaches to optimize immunosuppression regimens for the treatment or prophylaxis of acute GVHD by targeting PDCs and the Th17 response. Disclosures: No relevant conflicts of interest to declare.

scholarly journals B Cells Modulate Systemic Responses to Pneumocystis murina Lung Infection and Protect On-Demand Hematopoiesis via T Cell-Independent Innate Mechanisms when Type I Interferon Signaling Is Absent

2014 ◽  
Vol 83 (2) ◽  
pp. 743-758 ◽  
Author(s):  
Teri R. Hoyt ◽  
Erin Dobrinen ◽  
Irina Kochetkova ◽  
Nicole Meissner
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Lung Infection ◽  
Type I ◽  
Type I Ifn ◽  
Content Type ◽  
On Demand ◽  
Type I Ifns

HIV infection results in a complex immunodeficiency due to loss of CD4+T cells, impaired type I interferon (IFN) responses, and B cell dysfunctions causing susceptibility to opportunistic infections such asPneumocystis murinapneumonia and unexplained comorbidities, including bone marrow dysfunctions. Type I IFNs and B cells critically contribute to immunity toPneumocystislung infection. We recently also identified B cells as supporters of on-demand hematopoiesis followingPneumocystisinfection that would otherwise be hampered due to systemic immune effects initiated in the context of a defective type I IFN system. While studying the role of type I IFNs in immunity toPneumocystisinfection, we discovered that mice lacking both lymphocytes and type I IFN receptor (IFrag−/−) developed progressive bone marrow failure following infection, while lymphocyte-competent type I IFN receptor-deficient mice (IFNAR−/−) showed transient bone marrow depression and extramedullary hematopoiesis. Lymphocyte reconstitution of lymphocyte-deficient IFrag−/−mice pointed to B cells as a key player in bone marrow protection. Here we define how B cells protect on-demand hematopoiesis followingPneumocystis lung infection in our model. We demonstrate that adoptive transfer of B cells into IFrag−/−mice protects early hematopoietic progenitor activity during systemic responses toPneumocystisinfection, thus promoting replenishment of depleted bone marrow cells. This activity is independent of CD4+T cell help and B cell receptor specificity and does not require B cell migration to bone marrow. Furthermore, we show that B cells protect on-demand hematopoiesis in part by induction of interleukin-10 (IL-10)- and IL-27-mediated mechanisms. Thus, our data demonstrate an important immune modulatory role of B cells duringPneumocystislung infection that complement the modulatory role of type I IFNs to prevent systemic complications.

scholarly journals The Yin and Yang of Type I IFNs in Cancer Promotion and Immune Activation

Biology ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 856
Author(s):  
Martina Musella ◽  
Claudia Galassi ◽  
Nicoletta Manduca ◽  
Antonella Sistigu
Keyword(s):  
Deep Understanding ◽  
Type I Interferons ◽  
Host Immune System ◽  
Type I ◽  
Type I Ifn ◽  
Dual Nature ◽  
Adaptive Resistance ◽  
Type I Ifns ◽  
Yin And Yang

Type I Interferons (IFNs) are key regulators of natural and therapy-induced host defense against viral infection and cancer. Several years of remarkable progress in the field of oncoimmunology have revealed the dual nature of these cytokines. Hence, Type I IFNs may trigger anti-tumoral responses, while leading immune dysfunction and disease progression. This dichotomy relies on the duration and intensity of the transduced signaling, the nature of the unleashed IFN stimulated genes, and the subset of responding cells. Here, we discuss the role of Type I IFNs in the evolving relationship between the host immune system and cancer, as we offer a view of the therapeutic strategies that exploit and require an intact Type I IFN signaling, and the role of these cytokines in inducing adaptive resistance. A deep understanding of the complex, yet highly regulated, network of Type I IFN triggered molecular pathways will help find a timely and immune“logical” way to exploit these cytokines for anticancer therapy.

scholarly journals Actin Cytoskeleton Dynamics and Type I IFN-Mediated Immune Response: A Dangerous Liaison in Cancer?

Biology ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 913
Author(s):  
Paola Trono ◽  
Annalisa Tocci ◽  
Martina Musella ◽  
Antonella Sistigu ◽  
Paola Nisticò
Keyword(s):  
Immune Response ◽  
Actin Cytoskeleton ◽  
Cancer Treatment ◽  
Tissue Homeostasis ◽  
Type I ◽  
Type I Ifn ◽  
Anti Cancer ◽  
Complex Signaling ◽  
Cytoskeleton Dynamics

Chronic viral infection and cancer are closely inter-related and are both characterized by profound alteration of tissue homeostasis. The actin cytoskeleton dynamics highly participate in tissue homeostasis and act as a sensor leading to an immune-mediated anti-cancer and anti-viral response. Herein we highlight the crucial role of actin cytoskeleton dynamics in participating in a viral mimicry activation with profound effect in anti-tumor immune response. This still poorly explored field understands the cytoskeleton dynamics as a platform of complex signaling pathways which may regulate Type I IFN response in cancer. This emerging network needs to be elucidated to identify more effective anti-cancer strategies and to further advance the immuno-oncology field which has revolutionized the cancer treatment. For a progress to occur in this exciting arena we have to shed light on actin cytoskeleton related pathways and immune response. Herein we summarize the major findings, considering the double sword of the immune response and in particular the role of Type I IFN pathways in resistance to anti-cancer treatment.

scholarly journals Inhibition of Type I Interferon Signaling Abrogates Early Mycobacterium bovis Infection

2019 ◽  
Author(s):  
Jie Wang ◽  
Tariq Hussain ◽  
Kai Zhang ◽  
Yi Liao ◽  
Jiao Yao ◽  
...  
Keyword(s):  
Mycobacterium Bovis ◽  
T Cell Activation ◽  
Cell Activation ◽  
Defense Mechanism ◽  
Type I ◽  
Type I Ifn ◽  
Regulatory Pathways ◽  
Type I Ifns

Abstract Background: Mycobacterium bovis (M. bovis) is the principal causative agent of bovine tuberculosis; however, it may also cause serious infection in human being. Type I IFN is a key factor in reducing viral multiplication and modulating host immune response against viral infection. However, the regulatory pathways of Type I IFN signaling during M. bovis infection are not yet fully explored. Here, we investigate the role of Type I IFN signaling in the pathogenesis of M. bovis infection in mice. Methods: C57BL/6 mice were treated with IFNAR1-blocking antibody or Isotype control 24 hour before M. bovis infection. After 21 and 84 days of infection, mice were sacrificed and the role of Type I IFN signaling in the pathogenesis of M. bovis was investigated. ELISA and qRT-PCR were performed to detect the expression of Type I IFNs and related genes. Lung lesions induced by M. bovis were assessed by histopathological examination.Viable bacterial count was determined by CFU assay. Results: We observed an abundant expression of Type I IFNs in the serum and lung tissues of M. bovis infected mice. In vivo blockade of Type I IFN signaling reduced the recruitment of neutrophils to the lung tissue, mediated the activation of macrophages leading to an increased pro-inflammatory profile and regulated the inflammatory cytokine production. However, no impact was observed on T cell activation and recruitment in the early acute phase of infection. Additionally, blocking of type I IFN signaling reduced bacterial burden in the infected mice as compared to untreated infected mice. Conclusions: Altogether, our results reveal that Type I IFN mediates a balance between M. bovis-mediated inflammatory reaction and host defense mechanism. Thus, modulating Type I IFN signaling could be exploited as a therapeutic strategy against a large repertoire of inflammatory disorders including tuberculosis.

scholarly journals Innate Immune Response to Adenoviral Vectors Is Mediated by both Toll-Like Receptor-Dependent and -Independent Pathways

2007 ◽  
Vol 81 (7) ◽  
pp. 3170-3180 ◽  
Author(s):  
Jiangao Zhu ◽  
Xiaopei Huang ◽  
Yiping Yang
Keyword(s):  
Gene Therapy ◽  
Immune Response ◽  
Immune Responses ◽  
Innate Immune Response ◽  
Adenoviral Vectors ◽  
Innate Immune ◽  
Type I ◽  
Type I Ifn ◽  
Adaptive Immune ◽  
Type I Ifns

ABSTRACT Recombinant adenoviral vectors have been widely used for gene therapy applications and as vaccine vehicles for treating infectious diseases such as human immunodeficiency virus disease. The innate immune response to adenoviruses represents the most significant hurdle in clinical application of adenoviral vectors for gene therapy, but it is an attractive feature for vaccine development. How adenovirus activates innate immunity remains largely unknown. Here we showed that adenovirus elicited innate immune response through the induction of high levels of type I interferons (IFNs) by both plasmacytoid dendritic cells (pDCs) and non-pDCs such as conventional DCs and macrophages. The innate immune recognition of adenovirus by pDCs was mediated by Toll-like receptor 9 (TLR9) and was dependent on MyD88, whereas that by non-pDCs was TLR independent through cytosolic sensing of adenoviral DNA. Furthermore, type I IFNs were pivotal in innate and adaptive immune responses to adenovirus in vivo, and type I IFN blockade diminished immune responses, resulting in more stable transgene expression and reduction of inflammation. These findings indicate that adenovirus activates innate immunity by its DNA through TLR-dependent and -independent pathways in a cell type-specific fashion, and they highlight a critical role for type I IFNs in innate and adaptive immune responses to adenoviral vectors. Our results that suggest strategies to interfere with type I IFN pathway may improve the outcome of adenovirus-mediated gene therapy, whereas approaches to activate the type I IFN pathway may enhance vaccine potency.

scholarly journals Viral coinfection promotes tuberculosis immunopathogenesis by type I IFN signaling-dependent impediment of Th1 pulmonary influx

2021 ◽  
Author(s):  
Sung Jae Shin ◽  
Tae Gun Kang ◽  
Kee Woong Kwon ◽  
Kyung Soo Kim ◽  
Insuk Lee ◽  
...  
Keyword(s):  
Lymphocytic Choriomeningitis ◽  
Type I ◽  
Type I Ifn ◽  
Th1 Cell ◽  
Type I Ifns ◽  
Immunological Mechanisms ◽  
Negative Role ◽  
Ifn Γ ◽  
Viral Coinfection

Abstract Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is often exacerbated upon coinfection, but the underlying immunological mechanisms remain unclear. Here, to elucidate these mechanisms, we used a Mtb and lymphocytic choriomeningitis virus coinfection model. Viral coinfection significantly suppressed Mtb-specific IFN-γ production, with elevated bacterial loads and hyperinflammation in the lungs. Type I IFN signaling blockade rescued the Mtb-specific IFN-γ response and ameliorated lung immunopathology. Single-cell sequencing, tissue immunofluorescence staining, and adoptive transfer experiments revealed that type I IFN signaling produced in response to viral infection inhibited CXCL9/10 production in myeloid cells, resulting in impaired pulmonary migration of Mtb-specific CD4+ T cells from lymph nodes. Thus, virus coinfection-induced type I IFN signaling prior to the pulmonary localization of Mtb-specific Th1 cells exacerbates TB immunopathogenesis by impeding the Mtb-specific Th1 cell influx. Our study highlights another novel negative role of viral coinfection and/or type I IFNs in delaying Mtb-specific Th1 responses in the lung.

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