Influenza is a common contagious respiratory illness that affects people worldwide. Secondary bac... more Influenza is a common contagious respiratory illness that affects people worldwide. Secondary bacterial infection is a major complication during influenza infection that causes significant morbidity and mortality. We have previously shown that influenza induces type I interferon (IFN)-mediated inhibition of Type17 immune responses, resulting in exacerbation of bacterial burden during influenza and Staphylococcus aureus super-infection in mice. Here, we investigated the role of the signaling mediator, STAT2, downstream of type I IFN signaling in both influenza infection and bacterial super-infection. Influenza-infected STAT2−/− mice had increased weight loss, increased viral burden, and increased inflammatory responses when compared to influenza-infected WT mice. Despite an exaggerated inflammatory response to influenza infection alone, influenza and methicillin resistant S. aureus (MRSA) super-infected STAT2−/− mice had lower bacterial burden, morbidity, and mortality than WT mice. STAT2−/− mice had an increased expression of markers associated with M1 (classical) and M2 (alternative) macrophages in lung during influenza or influenza-bacterial super infection compared to WT mice. Next, we found neutralization of IFNγ or Arginase1 decreased bacterial clearance in STAT2−/− mice in influenza-bacterial super-infection, suggesting that both M1 and M2 phenotype mediate host defense during influenza-bacterial super-infection. These data demonstrate a clear role for type I IFN induced STAT2 signaling in suppression of macrophage function during influenza, MRSA super-infection. Further, these studies reveal novel mechanistic insight into the roles of macrophage subpopulations in pulmonary host defense.
Influenza is one of the most common causes of respiratory illness worldwide and can be complicate... more Influenza is one of the most common causes of respiratory illness worldwide and can be complicated by secondary bacterial pneumonia, which is a common cause of mortality. Influenza-induced “cytokine storm” is thought to play a role in lung pathogenesis during influenza infection. PPARγ is a member of nuclear hormone receptor superfamily that is known to enhance lipid and glucose metabolism, cellular differentiation and suppress the inflammatory immune response. Synthetic PPARγ agonists (thiazolidinedione, rosiglitazone) have been used clinically in the treatment of type II diabetes. In this study, we determined the effect of rosiglitazone in mice infected with influenza or influenza, methicillin-resistant Staphylococcus aureus (MRSA) super-infection. We found decreased influenza viral burden, decreased numbers of neutrophils and macrophages in bronchoalveolar lavage (BAL), and decreased production of IL-6, IL-12, CCL2, and CXCL10 in influenza-infected, rosiglitazone-treated mice whe...
Influenza is a common contagious respiratory illness that affects people worldwide. Secondary bac... more Influenza is a common contagious respiratory illness that affects people worldwide. Secondary bacterial infection is a major complication during influenza infection that causes significant morbidity and mortality. We have previously shown that influenza induces type I interferon (IFN)-mediated inhibition of Type17 immune responses, resulting in exacerbation of bacterial burden during influenza and Staphylococcus aureus super-infection in mice. Here, we investigated the role of the signaling mediator, STAT2, downstream of type I IFN signaling in both influenza infection and bacterial super-infection. Influenza-infected STAT2−/− mice had increased weight loss, increased viral burden, and increased inflammatory responses when compared to influenza-infected WT mice. Despite an exaggerated inflammatory response to influenza infection alone, influenza and methicillin resistant S. aureus (MRSA) super-infected STAT2−/− mice had lower bacterial burden, morbidity, and mortality than WT mice. ...
Influenza virus is among the most common causes of respiratory illness worldwide and can be compl... more Influenza virus is among the most common causes of respiratory illness worldwide and can be complicated by secondary bacterial pneumonia, a frequent cause of mortality. When influenza virus infects the lung, the innate immune response is activated, and interferons and inflammatory mediators are released. This “cytokine storm” is thought to play a role in influenza-induced lung pathogenesis. Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the nuclear hormone receptor super-family. PPARγ has numerous functions including enhancing lipid and glucose metabolism and cellular differentiation and suppressing inflammation. Synthetic PPARγ agonists (thiazolidinediones or glitazones) have been used clinically in the treatment of type II diabetes. Using data from the National Health and Nutrition Examination Survey (NHANES), diabetic participants taking rosiglitazone had an increased risk of mortality from influenza/pneumonia compared to those not taking the drug. We exa...
The development of a tuberculosis (TB) vaccine that induces sterilizing immunity to Mycobacterium... more The development of a tuberculosis (TB) vaccine that induces sterilizing immunity to Mycobacterium tuberculosis infection has been elusive. Absence of sterilizing immunity induced by TB vaccines may be due to delayed activation of mucosal dendritic cells (DCs), and subsequent delay in antigen presentation and activation of vaccine-induced CD4(+) T-cell responses. Here we show that pulmonary delivery of activated M. tuberculosis antigen-primed DCs into vaccinated mice, at the time of M. tuberculosis exposure, can overcome the delay in accumulation of vaccine-induced CD4(+) T-cell responses. In addition, activating endogenous host CD103(+) DCs and the CD40-CD40L pathway can similarly induce rapid accumulation of vaccine-induced lung CD4(+) T-cell responses and limit early M. tuberculosis growth. Thus, our study provides proof of concept that targeting mucosal DCs can accelerate vaccine-induced T-cell responses on M. tuberculosis infection, and provide insights to overcome bottlenecks i...
The identification of a new T cell subset referred to as T helper 17 (Th17) cells and its role in... more The identification of a new T cell subset referred to as T helper 17 (Th17) cells and its role in protective immunity against extracellular bacterial infections is well established. In contrast, initial studies suggested that the IL-23-IL-17 pathway was not required for protection against intracellular pathogens such as mycobacterial infections. However, recent studies demonstrate that Th17-IL-23 pathway may play a crucial role in protective immunity against other intracellular pathogens by regulating the innate and adaptive immune responses. The current outlook on the role of IL-23-IL-17 pathway in protective immunity to intracellular pathogens is discussed here.
The generation of effective type 1 T helper (Th1)‐cell responses is required for immunity against... more The generation of effective type 1 T helper (Th1)‐cell responses is required for immunity against intracellular bacteria. However, some intracellular bacteria require interleukin (IL)‐17 to drive Th1‐cell immunity and subsequent protective host immunity. Here, in a model of Mycobacterium bovis Bacille Calmette–Guerin (BCG) vaccination in mice, we demonstrate that the dependence on IL‐17 to drive Th1‐cell responses is a host mechanism to overcome bacteria‐induced IL‐10 inhibitory effects. We show that BCG‐induced prostaglandin‐E2 (PGE2) promotes the production of IL‐10 which limits Th1‐cell responses, while simultaneously inducing IL‐23 and Th17‐cell differentiation. The ability of IL‐17 to downregulate IL‐10 and induce IL‐12 production allows the generation of subsequent Th1‐cell responses. Accordingly, BCG‐induced Th17‐cell responses precede the generation of Th1‐cell responses in vivo, whereas the absence of the IL‐23 pathway decreases BCG vaccine‐induced Th17 and Th1‐cell immunit...
Influenza is a common contagious respiratory illness that affects people worldwide. Secondary bac... more Influenza is a common contagious respiratory illness that affects people worldwide. Secondary bacterial infection is a major complication during influenza infection that causes significant morbidity and mortality. We have previously shown that influenza induces type I interferon (IFN)-mediated inhibition of Type17 immune responses, resulting in exacerbation of bacterial burden during influenza and Staphylococcus aureus super-infection in mice. Here, we investigated the role of the signaling mediator, STAT2, downstream of type I IFN signaling in both influenza infection and bacterial super-infection. Influenza-infected STAT2−/− mice had increased weight loss, increased viral burden, and increased inflammatory responses when compared to influenza-infected WT mice. Despite an exaggerated inflammatory response to influenza infection alone, influenza and methicillin resistant S. aureus (MRSA) super-infected STAT2−/− mice had lower bacterial burden, morbidity, and mortality than WT mice. STAT2−/− mice had an increased expression of markers associated with M1 (classical) and M2 (alternative) macrophages in lung during influenza or influenza-bacterial super infection compared to WT mice. Next, we found neutralization of IFNγ or Arginase1 decreased bacterial clearance in STAT2−/− mice in influenza-bacterial super-infection, suggesting that both M1 and M2 phenotype mediate host defense during influenza-bacterial super-infection. These data demonstrate a clear role for type I IFN induced STAT2 signaling in suppression of macrophage function during influenza, MRSA super-infection. Further, these studies reveal novel mechanistic insight into the roles of macrophage subpopulations in pulmonary host defense.
Influenza is one of the most common causes of respiratory illness worldwide and can be complicate... more Influenza is one of the most common causes of respiratory illness worldwide and can be complicated by secondary bacterial pneumonia, which is a common cause of mortality. Influenza-induced “cytokine storm” is thought to play a role in lung pathogenesis during influenza infection. PPARγ is a member of nuclear hormone receptor superfamily that is known to enhance lipid and glucose metabolism, cellular differentiation and suppress the inflammatory immune response. Synthetic PPARγ agonists (thiazolidinedione, rosiglitazone) have been used clinically in the treatment of type II diabetes. In this study, we determined the effect of rosiglitazone in mice infected with influenza or influenza, methicillin-resistant Staphylococcus aureus (MRSA) super-infection. We found decreased influenza viral burden, decreased numbers of neutrophils and macrophages in bronchoalveolar lavage (BAL), and decreased production of IL-6, IL-12, CCL2, and CXCL10 in influenza-infected, rosiglitazone-treated mice whe...
Influenza is a common contagious respiratory illness that affects people worldwide. Secondary bac... more Influenza is a common contagious respiratory illness that affects people worldwide. Secondary bacterial infection is a major complication during influenza infection that causes significant morbidity and mortality. We have previously shown that influenza induces type I interferon (IFN)-mediated inhibition of Type17 immune responses, resulting in exacerbation of bacterial burden during influenza and Staphylococcus aureus super-infection in mice. Here, we investigated the role of the signaling mediator, STAT2, downstream of type I IFN signaling in both influenza infection and bacterial super-infection. Influenza-infected STAT2−/− mice had increased weight loss, increased viral burden, and increased inflammatory responses when compared to influenza-infected WT mice. Despite an exaggerated inflammatory response to influenza infection alone, influenza and methicillin resistant S. aureus (MRSA) super-infected STAT2−/− mice had lower bacterial burden, morbidity, and mortality than WT mice. ...
Influenza virus is among the most common causes of respiratory illness worldwide and can be compl... more Influenza virus is among the most common causes of respiratory illness worldwide and can be complicated by secondary bacterial pneumonia, a frequent cause of mortality. When influenza virus infects the lung, the innate immune response is activated, and interferons and inflammatory mediators are released. This “cytokine storm” is thought to play a role in influenza-induced lung pathogenesis. Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the nuclear hormone receptor super-family. PPARγ has numerous functions including enhancing lipid and glucose metabolism and cellular differentiation and suppressing inflammation. Synthetic PPARγ agonists (thiazolidinediones or glitazones) have been used clinically in the treatment of type II diabetes. Using data from the National Health and Nutrition Examination Survey (NHANES), diabetic participants taking rosiglitazone had an increased risk of mortality from influenza/pneumonia compared to those not taking the drug. We exa...
The development of a tuberculosis (TB) vaccine that induces sterilizing immunity to Mycobacterium... more The development of a tuberculosis (TB) vaccine that induces sterilizing immunity to Mycobacterium tuberculosis infection has been elusive. Absence of sterilizing immunity induced by TB vaccines may be due to delayed activation of mucosal dendritic cells (DCs), and subsequent delay in antigen presentation and activation of vaccine-induced CD4(+) T-cell responses. Here we show that pulmonary delivery of activated M. tuberculosis antigen-primed DCs into vaccinated mice, at the time of M. tuberculosis exposure, can overcome the delay in accumulation of vaccine-induced CD4(+) T-cell responses. In addition, activating endogenous host CD103(+) DCs and the CD40-CD40L pathway can similarly induce rapid accumulation of vaccine-induced lung CD4(+) T-cell responses and limit early M. tuberculosis growth. Thus, our study provides proof of concept that targeting mucosal DCs can accelerate vaccine-induced T-cell responses on M. tuberculosis infection, and provide insights to overcome bottlenecks i...
The identification of a new T cell subset referred to as T helper 17 (Th17) cells and its role in... more The identification of a new T cell subset referred to as T helper 17 (Th17) cells and its role in protective immunity against extracellular bacterial infections is well established. In contrast, initial studies suggested that the IL-23-IL-17 pathway was not required for protection against intracellular pathogens such as mycobacterial infections. However, recent studies demonstrate that Th17-IL-23 pathway may play a crucial role in protective immunity against other intracellular pathogens by regulating the innate and adaptive immune responses. The current outlook on the role of IL-23-IL-17 pathway in protective immunity to intracellular pathogens is discussed here.
The generation of effective type 1 T helper (Th1)‐cell responses is required for immunity against... more The generation of effective type 1 T helper (Th1)‐cell responses is required for immunity against intracellular bacteria. However, some intracellular bacteria require interleukin (IL)‐17 to drive Th1‐cell immunity and subsequent protective host immunity. Here, in a model of Mycobacterium bovis Bacille Calmette–Guerin (BCG) vaccination in mice, we demonstrate that the dependence on IL‐17 to drive Th1‐cell responses is a host mechanism to overcome bacteria‐induced IL‐10 inhibitory effects. We show that BCG‐induced prostaglandin‐E2 (PGE2) promotes the production of IL‐10 which limits Th1‐cell responses, while simultaneously inducing IL‐23 and Th17‐cell differentiation. The ability of IL‐17 to downregulate IL‐10 and induce IL‐12 production allows the generation of subsequent Th1‐cell responses. Accordingly, BCG‐induced Th17‐cell responses precede the generation of Th1‐cell responses in vivo, whereas the absence of the IL‐23 pathway decreases BCG vaccine‐induced Th17 and Th1‐cell immunit...
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