The Experts below are selected from a list of 6321 Experts worldwide ranked by ideXlab platform
Jordi B. Torrelles - One of the best experts on this subject based on the ideXlab platform.
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The human Lung Mucosa drives differential Mycobacterium tuberculosis infection outcome in the alveolar epithelium.
Mucosal immunology, 2019Co-Authors: Julia M. Scordo, Jesus Arcos, Angelica Olmo-fontanez, Anwari Akhter, S Sidiki, H V Kelley, Mark D. Wewers, Jordi B. TorrellesAbstract:Mycobacterium tuberculosis (M.tb) is deposited into the alveolus where it first encounters the alveolar lining fluid (ALF) prior contacts host cells. We demonstrated that M.tb-exposure to human ALF alters its cell surface, driving better M.tb infection control by professional phagocytes. Contrary to these findings, our results with non-professional phagocytes alveolar epithelial cells (ATs) define two distinct subsets of human ALFs; where M.tb exposure to Low (L)-ALF or High(H)-ALF results in low or high intracellular bacterial growth rates in ATs, respectively. H-ALF exposed-M.tb growth within ATs was independent of M.tb-uptake, M.tb-trafficking, and M.tb-infection induced cytotoxicity; however, it was associated with enhanced bacterial replication within LAMP-1+/ABCA1+ compartments. H-ALF exposed-M.tb infection of ATs decreased AT immune mediator production, decreased AT surface adhesion expression, and downregulated macrophage inflammatory responses. Composition analysis of H-ALF vs. L-ALF showed H-ALF with higher protein tyrosine nitration and less functional ALF-innate proteins important in M.tb pathogenesis. Replenishment of H-ALF with functional ALF-innate proteins reversed the H-ALF-M.tb growth rate to the levels observed for L-ALF-M.tb. These results indicate that dysfunctionality of innate proteins in the H-ALF phenotype promotes M.tb replication within ATs, while limiting inflammation and phagocyte activation, thus potentiating ATs as a reservoir for M.tb replication and survival.
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Exposure to human alveolar lining fluid enhances Mycobacterium bovis BCG vaccine efficacy against Mycobacterium tuberculosis infection in a CD8 + T-cell-dependent manner
Mucosal immunology, 2017Co-Authors: Juan I. Moliva, Joanne Turner, Mark D. Wewers, Austin P. Hossfeld, Cynthia H. Canan, Varun Dwivedi, Gillian Beamer, Jordi B. TorrellesAbstract:Current tuberculosis (TB) treatments include chemotherapy and preventative vaccination with Mycobacterium bovis Bacillus Calmette-Guerin (BCG). In humans, however, BCG vaccination fails to fully protect against pulmonary TB. Few studies have considered the impact of the human Lung Mucosa (alveolar lining fluid (ALF)), which modifies the Mycobacterium tuberculosis (M.tb) cell wall, revealing alternate antigenic epitopes on the bacterium surface that alter its pathogenicity. We hypothesized that ALF-induced modification of BCG would induce better protection against aerosol infection with M.tb. Here we vaccinated mice with ALF-exposed BCG, mimicking the mycobacterial cell surface properties that would be present in the Lung during M.tb infection. ALF-exposed BCG-vaccinated mice were more effective at reducing M.tb bacterial burden in the Lung and spleen, and had reduced Lung inflammation at late stages of M.tb infection. Improved BCG efficacy was associated with increased numbers of memory CD8+ T cells, and CD8+ T cells with the potential to produce interferon-γ in the Lung in response to M.tb challenge. Depletion studies confirmed an essential role for CD8+ T cells in controlling M.tb bacterial burden. We conclude that ALF modifications to the M.tb cell wall in vivo are relevant in the context of vaccine design.
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Mycobacterium tuberculosis Cell Wall Fragments Released upon Bacterial Contact with the Human Lung Mucosa Alter the Neutrophil Response to Infection
Frontiers in immunology, 2017Co-Authors: Julia M. Scordo, Jesus Arcos, Lauren E. Diangelo, Smitha J. Sasindran, H V Kelley, Ellie Youngmin, Mark D. Wewers, Shu-hua Wang, Joan-miquel Balada-llasat, Jordi B. TorrellesAbstract:In 2016 the World Health Organization (WHO) reported that one person dies of tuberculosis every 21 seconds. A host environment that Mycobacterium tuberculosis (M.tb) finds during its route of infection is the Lung Mucosa bathing the alveolar space located in the deepest regions of the Lungs. We published that human Lung Mucosa, or alveolar lining fluid (ALF), contains an array of hydrolytic enzymes that can significantly alter the M.tb surface during infection by cleaving off parts of its cell wall. This interaction results in two different outcomes: modifications on the M.tb cell wall surface and release of M.tb cell wall fragments into the environment. Typically, one of the first host immune cells at the site of M.tb infection is the neutrophil. Neutrophils can mount an extracellular and intracellular innate immune response to M.tb during infection. We hypothesized that exposure of neutrophils to ALF-induced M.tb released cell wall fragments would prime neutrophils to control M.tb infection better. Our results show that ALF-fragments activate neutrophils leading to an increased production of inflammatory cytokines and oxidative radicals. However, neutrophil exposure to these fragments reduces production of chemoattractants (i.e. Interleukin-8), and degranulation, with the subsequent reduction of myeloperoxidase release; and does not induce cytotoxicity. Unexpectedly, these ALF-fragments derived modulations in neutrophil activity do not further, either positively or negatively, contribute to the intracellular control of M.tb growth during infection. However, secreted products from neutrophils primed with ALF-fragments are capable of regulating the activity of resting macrophages. These results indicate that ALF-induced M.tb fragments could further contribute to the control of M.tb growth and local killing by resident neutrophils by switching on the total oxidative response and limiting migration of neutrophils to the infection site.
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Age-associated oxidation of innate immune proteins in the Lung Mucosa alters the host response to Mycobacterium tuberculosis
Journal of Immunology, 2016Co-Authors: Juan I. Moliva, Smitha J. Sasindran, Joanne Turner, Murugesan V. S. Rajaram, Larry S. Schlesinger, Jordi B. TorrellesAbstract:Age-associated immune changes are a risk factor for the development of tuberculosis (TB); however the phenomenon of inflammaging, a state of heightened systemic inflammation observed in the elderly, particularly within the Lung Mucosa has not been addressed. Mycobacterium tuberculosis (M.tb) infection results in bacterial deposition in the Lung alveoli where they are bathed in alveolar lining fluid (ALF). ALF contains soluble innate factors that mediate the M.tb-host cell encounter and subsequent immune response. Recent studies indicate that local inflammation and oxidation occur within the ALF. We hypothesize that ALF components lose their function as we age, and this deficiency favors the establishment of M.tb infection. Previously, we reported increased oxidation of proteins within ALF from human adult (ages 25–44) and elderly (ages >65) populations, in addition to elevated basal levels of inflammatory cytokines and complement components. Here, we extended our findings to explore the impact of adult or elderly ALF during M.tb infection. Although the levels of SP-A and C3 were elevated in elderly ALF, their binding to M.tb was reduced, suggesting a defect in innate immune function with age. To evaluate the impact of ALF age-associated changes in vivo, mice were infected with M.tb pre-exposed to adult or elderly ALF. Mice infected with elderly ALF-M.tb had significantly increased bacterial growth within the Lung and spleen compared to adult ALF-M.tb infected mice, suggesting that loss of innate immune function within ALF could have long term consequences in controlling M.tb infection. We conclude that M.tb may benefit from the declining host defense function of the Lung Mucosa in the elderly, driving host susceptibility to TB.
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Lung Mucosa Lining Fluid Modification of Mycobacterium tuberculosis to Reprogram Human Neutrophil Killing Mechanisms
The Journal of infectious diseases, 2015Co-Authors: Jesus Arcos, Lauren E. Diangelo, Julia M. Scordo, Smitha J. Sasindran, Juan I. Moliva, Joanne Turner, Jordi B. TorrellesAbstract:We have shown that human alveolar lining fluid (ALF) contains homeostatic hydrolases capable of altering the Mycobacterium tuberculosis cell wall and subsequently its interaction with human macrophages. Neutrophils are also an integral part of the host immune response to M. tuberculosis infection. Here we show that the human Lung Mucosa influences M. tuberculosis interaction with neutrophils, enhancing the intracellular killing of ALF-exposed M. tuberculosis and up-regulating the expression of tumor necrosis factor and interleukin 8. In contrast, ALF-exposed M. tuberculosis does not induce neutrophil apoptosis or necrosis, degranulation, or release of extracellular traps, and it decreases the oxidative response. These results suggest an important role for the human alveolar Mucosa: increasing the innate capacity of the neutrophil to recognize and kill M. tuberculosis by favoring the use of intracellular mechanisms, while at the same time limiting neutrophil extracellular inflammatory responses to minimize their associated tissue damage.
Julia M. Scordo - One of the best experts on this subject based on the ideXlab platform.
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The Lung Mucosa Environment in the Elderly Increases Host Susceptibility to Mycobacterium tuberculosis Infection
The Journal of infectious diseases, 2019Co-Authors: Juan I. Moliva, Julia M. Scordo, Smitha J. Sasindran, Michael A Duncan, Angelica Olmo-fontanez, Anwari Akhter, Eusondia Arnett, Russell Ault, Abul K. Azad, Maria J. MontoyaAbstract:As we age, there is an increased risk for the development of tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) infection. Few studies consider that age-associated changes in the alveolar lining fluid (ALF) may increase susceptibility by altering soluble mediators of innate immunity. We assessed the impact of adult or elderly human ALF during Mtb infection in vitro and in vivo. We identified amplification of pro-oxidative and proinflammatory pathways in elderly ALF and decreased binding capability of surfactant-associated surfactant protein A (SP-A) and surfactant protein D (SP-D) to Mtb. Human macrophages infected with elderly ALF-exposed Mtb had reduced control and fewer phagosome-lysosome fusion events, which was reversed when elderly ALF was replenished with functional SP-A/SP-D. In vivo, exposure to elderly ALF exacerbated Mtb infection in young mice. Our studies demonstrate how the pulmonary environment changes as we age and suggest that Mtb may benefit from declining host defenses in the Lung Mucosa of the elderly.
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The human Lung Mucosa drives differential Mycobacterium tuberculosis infection outcome in the alveolar epithelium.
Mucosal immunology, 2019Co-Authors: Julia M. Scordo, Jesus Arcos, Angelica Olmo-fontanez, Anwari Akhter, S Sidiki, H V Kelley, Mark D. Wewers, Jordi B. TorrellesAbstract:Mycobacterium tuberculosis (M.tb) is deposited into the alveolus where it first encounters the alveolar lining fluid (ALF) prior contacts host cells. We demonstrated that M.tb-exposure to human ALF alters its cell surface, driving better M.tb infection control by professional phagocytes. Contrary to these findings, our results with non-professional phagocytes alveolar epithelial cells (ATs) define two distinct subsets of human ALFs; where M.tb exposure to Low (L)-ALF or High(H)-ALF results in low or high intracellular bacterial growth rates in ATs, respectively. H-ALF exposed-M.tb growth within ATs was independent of M.tb-uptake, M.tb-trafficking, and M.tb-infection induced cytotoxicity; however, it was associated with enhanced bacterial replication within LAMP-1+/ABCA1+ compartments. H-ALF exposed-M.tb infection of ATs decreased AT immune mediator production, decreased AT surface adhesion expression, and downregulated macrophage inflammatory responses. Composition analysis of H-ALF vs. L-ALF showed H-ALF with higher protein tyrosine nitration and less functional ALF-innate proteins important in M.tb pathogenesis. Replenishment of H-ALF with functional ALF-innate proteins reversed the H-ALF-M.tb growth rate to the levels observed for L-ALF-M.tb. These results indicate that dysfunctionality of innate proteins in the H-ALF phenotype promotes M.tb replication within ATs, while limiting inflammation and phagocyte activation, thus potentiating ATs as a reservoir for M.tb replication and survival.
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Mycobacterium tuberculosis Cell Wall Fragments Released upon Bacterial Contact with the Human Lung Mucosa Alter the Neutrophil Response to Infection
Frontiers in immunology, 2017Co-Authors: Julia M. Scordo, Jesus Arcos, Lauren E. Diangelo, Smitha J. Sasindran, H V Kelley, Ellie Youngmin, Mark D. Wewers, Shu-hua Wang, Joan-miquel Balada-llasat, Jordi B. TorrellesAbstract:In 2016 the World Health Organization (WHO) reported that one person dies of tuberculosis every 21 seconds. A host environment that Mycobacterium tuberculosis (M.tb) finds during its route of infection is the Lung Mucosa bathing the alveolar space located in the deepest regions of the Lungs. We published that human Lung Mucosa, or alveolar lining fluid (ALF), contains an array of hydrolytic enzymes that can significantly alter the M.tb surface during infection by cleaving off parts of its cell wall. This interaction results in two different outcomes: modifications on the M.tb cell wall surface and release of M.tb cell wall fragments into the environment. Typically, one of the first host immune cells at the site of M.tb infection is the neutrophil. Neutrophils can mount an extracellular and intracellular innate immune response to M.tb during infection. We hypothesized that exposure of neutrophils to ALF-induced M.tb released cell wall fragments would prime neutrophils to control M.tb infection better. Our results show that ALF-fragments activate neutrophils leading to an increased production of inflammatory cytokines and oxidative radicals. However, neutrophil exposure to these fragments reduces production of chemoattractants (i.e. Interleukin-8), and degranulation, with the subsequent reduction of myeloperoxidase release; and does not induce cytotoxicity. Unexpectedly, these ALF-fragments derived modulations in neutrophil activity do not further, either positively or negatively, contribute to the intracellular control of M.tb growth during infection. However, secreted products from neutrophils primed with ALF-fragments are capable of regulating the activity of resting macrophages. These results indicate that ALF-induced M.tb fragments could further contribute to the control of M.tb growth and local killing by resident neutrophils by switching on the total oxidative response and limiting migration of neutrophils to the infection site.
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Lung Mucosa Lining Fluid Modification of Mycobacterium tuberculosis to Reprogram Human Neutrophil Killing Mechanisms
The Journal of infectious diseases, 2015Co-Authors: Jesus Arcos, Lauren E. Diangelo, Julia M. Scordo, Smitha J. Sasindran, Juan I. Moliva, Joanne Turner, Jordi B. TorrellesAbstract:We have shown that human alveolar lining fluid (ALF) contains homeostatic hydrolases capable of altering the Mycobacterium tuberculosis cell wall and subsequently its interaction with human macrophages. Neutrophils are also an integral part of the host immune response to M. tuberculosis infection. Here we show that the human Lung Mucosa influences M. tuberculosis interaction with neutrophils, enhancing the intracellular killing of ALF-exposed M. tuberculosis and up-regulating the expression of tumor necrosis factor and interleukin 8. In contrast, ALF-exposed M. tuberculosis does not induce neutrophil apoptosis or necrosis, degranulation, or release of extracellular traps, and it decreases the oxidative response. These results suggest an important role for the human alveolar Mucosa: increasing the innate capacity of the neutrophil to recognize and kill M. tuberculosis by favoring the use of intracellular mechanisms, while at the same time limiting neutrophil extracellular inflammatory responses to minimize their associated tissue damage.
Juan I. Moliva - One of the best experts on this subject based on the ideXlab platform.
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The Lung Mucosa Environment in the Elderly Increases Host Susceptibility to Mycobacterium tuberculosis Infection
The Journal of infectious diseases, 2019Co-Authors: Juan I. Moliva, Julia M. Scordo, Smitha J. Sasindran, Michael A Duncan, Angelica Olmo-fontanez, Anwari Akhter, Eusondia Arnett, Russell Ault, Abul K. Azad, Maria J. MontoyaAbstract:As we age, there is an increased risk for the development of tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) infection. Few studies consider that age-associated changes in the alveolar lining fluid (ALF) may increase susceptibility by altering soluble mediators of innate immunity. We assessed the impact of adult or elderly human ALF during Mtb infection in vitro and in vivo. We identified amplification of pro-oxidative and proinflammatory pathways in elderly ALF and decreased binding capability of surfactant-associated surfactant protein A (SP-A) and surfactant protein D (SP-D) to Mtb. Human macrophages infected with elderly ALF-exposed Mtb had reduced control and fewer phagosome-lysosome fusion events, which was reversed when elderly ALF was replenished with functional SP-A/SP-D. In vivo, exposure to elderly ALF exacerbated Mtb infection in young mice. Our studies demonstrate how the pulmonary environment changes as we age and suggest that Mtb may benefit from declining host defenses in the Lung Mucosa of the elderly.
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Exposure to human alveolar lining fluid enhances Mycobacterium bovis BCG vaccine efficacy against Mycobacterium tuberculosis infection in a CD8 + T-cell-dependent manner
Mucosal immunology, 2017Co-Authors: Juan I. Moliva, Joanne Turner, Mark D. Wewers, Austin P. Hossfeld, Cynthia H. Canan, Varun Dwivedi, Gillian Beamer, Jordi B. TorrellesAbstract:Current tuberculosis (TB) treatments include chemotherapy and preventative vaccination with Mycobacterium bovis Bacillus Calmette-Guerin (BCG). In humans, however, BCG vaccination fails to fully protect against pulmonary TB. Few studies have considered the impact of the human Lung Mucosa (alveolar lining fluid (ALF)), which modifies the Mycobacterium tuberculosis (M.tb) cell wall, revealing alternate antigenic epitopes on the bacterium surface that alter its pathogenicity. We hypothesized that ALF-induced modification of BCG would induce better protection against aerosol infection with M.tb. Here we vaccinated mice with ALF-exposed BCG, mimicking the mycobacterial cell surface properties that would be present in the Lung during M.tb infection. ALF-exposed BCG-vaccinated mice were more effective at reducing M.tb bacterial burden in the Lung and spleen, and had reduced Lung inflammation at late stages of M.tb infection. Improved BCG efficacy was associated with increased numbers of memory CD8+ T cells, and CD8+ T cells with the potential to produce interferon-γ in the Lung in response to M.tb challenge. Depletion studies confirmed an essential role for CD8+ T cells in controlling M.tb bacterial burden. We conclude that ALF modifications to the M.tb cell wall in vivo are relevant in the context of vaccine design.
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Age-associated oxidation of innate immune proteins in the Lung Mucosa alters the host response to Mycobacterium tuberculosis
Journal of Immunology, 2016Co-Authors: Juan I. Moliva, Smitha J. Sasindran, Joanne Turner, Murugesan V. S. Rajaram, Larry S. Schlesinger, Jordi B. TorrellesAbstract:Age-associated immune changes are a risk factor for the development of tuberculosis (TB); however the phenomenon of inflammaging, a state of heightened systemic inflammation observed in the elderly, particularly within the Lung Mucosa has not been addressed. Mycobacterium tuberculosis (M.tb) infection results in bacterial deposition in the Lung alveoli where they are bathed in alveolar lining fluid (ALF). ALF contains soluble innate factors that mediate the M.tb-host cell encounter and subsequent immune response. Recent studies indicate that local inflammation and oxidation occur within the ALF. We hypothesize that ALF components lose their function as we age, and this deficiency favors the establishment of M.tb infection. Previously, we reported increased oxidation of proteins within ALF from human adult (ages 25–44) and elderly (ages >65) populations, in addition to elevated basal levels of inflammatory cytokines and complement components. Here, we extended our findings to explore the impact of adult or elderly ALF during M.tb infection. Although the levels of SP-A and C3 were elevated in elderly ALF, their binding to M.tb was reduced, suggesting a defect in innate immune function with age. To evaluate the impact of ALF age-associated changes in vivo, mice were infected with M.tb pre-exposed to adult or elderly ALF. Mice infected with elderly ALF-M.tb had significantly increased bacterial growth within the Lung and spleen compared to adult ALF-M.tb infected mice, suggesting that loss of innate immune function within ALF could have long term consequences in controlling M.tb infection. We conclude that M.tb may benefit from the declining host defense function of the Lung Mucosa in the elderly, driving host susceptibility to TB.
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Lung Mucosa Lining Fluid Modification of Mycobacterium tuberculosis to Reprogram Human Neutrophil Killing Mechanisms
The Journal of infectious diseases, 2015Co-Authors: Jesus Arcos, Lauren E. Diangelo, Julia M. Scordo, Smitha J. Sasindran, Juan I. Moliva, Joanne Turner, Jordi B. TorrellesAbstract:We have shown that human alveolar lining fluid (ALF) contains homeostatic hydrolases capable of altering the Mycobacterium tuberculosis cell wall and subsequently its interaction with human macrophages. Neutrophils are also an integral part of the host immune response to M. tuberculosis infection. Here we show that the human Lung Mucosa influences M. tuberculosis interaction with neutrophils, enhancing the intracellular killing of ALF-exposed M. tuberculosis and up-regulating the expression of tumor necrosis factor and interleukin 8. In contrast, ALF-exposed M. tuberculosis does not induce neutrophil apoptosis or necrosis, degranulation, or release of extracellular traps, and it decreases the oxidative response. These results suggest an important role for the human alveolar Mucosa: increasing the innate capacity of the neutrophil to recognize and kill M. tuberculosis by favoring the use of intracellular mechanisms, while at the same time limiting neutrophil extracellular inflammatory responses to minimize their associated tissue damage.
Smitha J. Sasindran - One of the best experts on this subject based on the ideXlab platform.
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The Lung Mucosa Environment in the Elderly Increases Host Susceptibility to Mycobacterium tuberculosis Infection
The Journal of infectious diseases, 2019Co-Authors: Juan I. Moliva, Julia M. Scordo, Smitha J. Sasindran, Michael A Duncan, Angelica Olmo-fontanez, Anwari Akhter, Eusondia Arnett, Russell Ault, Abul K. Azad, Maria J. MontoyaAbstract:As we age, there is an increased risk for the development of tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) infection. Few studies consider that age-associated changes in the alveolar lining fluid (ALF) may increase susceptibility by altering soluble mediators of innate immunity. We assessed the impact of adult or elderly human ALF during Mtb infection in vitro and in vivo. We identified amplification of pro-oxidative and proinflammatory pathways in elderly ALF and decreased binding capability of surfactant-associated surfactant protein A (SP-A) and surfactant protein D (SP-D) to Mtb. Human macrophages infected with elderly ALF-exposed Mtb had reduced control and fewer phagosome-lysosome fusion events, which was reversed when elderly ALF was replenished with functional SP-A/SP-D. In vivo, exposure to elderly ALF exacerbated Mtb infection in young mice. Our studies demonstrate how the pulmonary environment changes as we age and suggest that Mtb may benefit from declining host defenses in the Lung Mucosa of the elderly.
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Mycobacterium tuberculosis Cell Wall Fragments Released upon Bacterial Contact with the Human Lung Mucosa Alter the Neutrophil Response to Infection
Frontiers in immunology, 2017Co-Authors: Julia M. Scordo, Jesus Arcos, Lauren E. Diangelo, Smitha J. Sasindran, H V Kelley, Ellie Youngmin, Mark D. Wewers, Shu-hua Wang, Joan-miquel Balada-llasat, Jordi B. TorrellesAbstract:In 2016 the World Health Organization (WHO) reported that one person dies of tuberculosis every 21 seconds. A host environment that Mycobacterium tuberculosis (M.tb) finds during its route of infection is the Lung Mucosa bathing the alveolar space located in the deepest regions of the Lungs. We published that human Lung Mucosa, or alveolar lining fluid (ALF), contains an array of hydrolytic enzymes that can significantly alter the M.tb surface during infection by cleaving off parts of its cell wall. This interaction results in two different outcomes: modifications on the M.tb cell wall surface and release of M.tb cell wall fragments into the environment. Typically, one of the first host immune cells at the site of M.tb infection is the neutrophil. Neutrophils can mount an extracellular and intracellular innate immune response to M.tb during infection. We hypothesized that exposure of neutrophils to ALF-induced M.tb released cell wall fragments would prime neutrophils to control M.tb infection better. Our results show that ALF-fragments activate neutrophils leading to an increased production of inflammatory cytokines and oxidative radicals. However, neutrophil exposure to these fragments reduces production of chemoattractants (i.e. Interleukin-8), and degranulation, with the subsequent reduction of myeloperoxidase release; and does not induce cytotoxicity. Unexpectedly, these ALF-fragments derived modulations in neutrophil activity do not further, either positively or negatively, contribute to the intracellular control of M.tb growth during infection. However, secreted products from neutrophils primed with ALF-fragments are capable of regulating the activity of resting macrophages. These results indicate that ALF-induced M.tb fragments could further contribute to the control of M.tb growth and local killing by resident neutrophils by switching on the total oxidative response and limiting migration of neutrophils to the infection site.
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Age-associated oxidation of innate immune proteins in the Lung Mucosa alters the host response to Mycobacterium tuberculosis
Journal of Immunology, 2016Co-Authors: Juan I. Moliva, Smitha J. Sasindran, Joanne Turner, Murugesan V. S. Rajaram, Larry S. Schlesinger, Jordi B. TorrellesAbstract:Age-associated immune changes are a risk factor for the development of tuberculosis (TB); however the phenomenon of inflammaging, a state of heightened systemic inflammation observed in the elderly, particularly within the Lung Mucosa has not been addressed. Mycobacterium tuberculosis (M.tb) infection results in bacterial deposition in the Lung alveoli where they are bathed in alveolar lining fluid (ALF). ALF contains soluble innate factors that mediate the M.tb-host cell encounter and subsequent immune response. Recent studies indicate that local inflammation and oxidation occur within the ALF. We hypothesize that ALF components lose their function as we age, and this deficiency favors the establishment of M.tb infection. Previously, we reported increased oxidation of proteins within ALF from human adult (ages 25–44) and elderly (ages >65) populations, in addition to elevated basal levels of inflammatory cytokines and complement components. Here, we extended our findings to explore the impact of adult or elderly ALF during M.tb infection. Although the levels of SP-A and C3 were elevated in elderly ALF, their binding to M.tb was reduced, suggesting a defect in innate immune function with age. To evaluate the impact of ALF age-associated changes in vivo, mice were infected with M.tb pre-exposed to adult or elderly ALF. Mice infected with elderly ALF-M.tb had significantly increased bacterial growth within the Lung and spleen compared to adult ALF-M.tb infected mice, suggesting that loss of innate immune function within ALF could have long term consequences in controlling M.tb infection. We conclude that M.tb may benefit from the declining host defense function of the Lung Mucosa in the elderly, driving host susceptibility to TB.
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Lung Mucosa Lining Fluid Modification of Mycobacterium tuberculosis to Reprogram Human Neutrophil Killing Mechanisms
The Journal of infectious diseases, 2015Co-Authors: Jesus Arcos, Lauren E. Diangelo, Julia M. Scordo, Smitha J. Sasindran, Juan I. Moliva, Joanne Turner, Jordi B. TorrellesAbstract:We have shown that human alveolar lining fluid (ALF) contains homeostatic hydrolases capable of altering the Mycobacterium tuberculosis cell wall and subsequently its interaction with human macrophages. Neutrophils are also an integral part of the host immune response to M. tuberculosis infection. Here we show that the human Lung Mucosa influences M. tuberculosis interaction with neutrophils, enhancing the intracellular killing of ALF-exposed M. tuberculosis and up-regulating the expression of tumor necrosis factor and interleukin 8. In contrast, ALF-exposed M. tuberculosis does not induce neutrophil apoptosis or necrosis, degranulation, or release of extracellular traps, and it decreases the oxidative response. These results suggest an important role for the human alveolar Mucosa: increasing the innate capacity of the neutrophil to recognize and kill M. tuberculosis by favoring the use of intracellular mechanisms, while at the same time limiting neutrophil extracellular inflammatory responses to minimize their associated tissue damage.
Adam K Wheatley - One of the best experts on this subject based on the ideXlab platform.
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Inducible Bronchus-Associated Lymphoid Tissues (iBALT) Serve as Sites of B Cell Selection and Maturation Following Influenza Infection in Mice
Frontiers in Immunology, 2019Co-Authors: Robyn Esterbauer, Hillary A. Vanderven, Stephen J Kent, Jennifer A Juno, Adam K WheatleyAbstract:Seasonally recurrent influenza virus infections are a significant cause of global morbidity and mortality. In murine models, primary influenza infection in the respiratory tract elicits potent humoral responses concentrated in the draining mediastinal lymph node and the spleen. In addition to immunity within secondary lymphoid organs (SLO), pulmonary infection is also associated with formation of ectopic inducible bronchus-associated tissues (iBALT) in the Lung. These structures display a lymphoid organization, but their function and protective benefits remain unclear. Here we examined the phenotype, transcriptional profile and antigen specificity of B cell populations forming iBALT in influenza infected mice. We show that the cellular composition of iBALT was comparable to SLO, containing populations of follicular dendritic cells (FDC), T-follicular helper (Tfh) cells, and germinal center (GC)-like B cells with classical dark- and light-zone polarization. Transcriptional profiles of GC B cells in iBALT and SLO were conserved regardless of anatomical localization. The architecture of iBALT was pleiomorphic and less structurally defined than SLO. Nevertheless, we show that GC-like structures within iBALT serve as a distinct niche that independently support the maturation and selection of B cells primarily targeted against the influenza virus nucleoprotein. Our findings suggest that iBALT, which are positioned at the frontline of the Lung Mucosa, drive long-lived, and unique GC reactions that contribute to the diversity of the humoral response targeting influenza.
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Image_2_Inducible Bronchus-Associated Lymphoid Tissues (iBALT) Serve as Sites of B Cell Selection and Maturation Following Influenza Infection in Mice.tiff
2019Co-Authors: Hyon Xhi Tan, Hillary A. Vanderven, Robyn Esterbauer, Stephen J Kent, Jennifer A Juno, Adam K WheatleyAbstract:Seasonally recurrent influenza virus infections are a significant cause of global morbidity and mortality. In murine models, primary influenza infection in the respiratory tract elicits potent humoral responses concentrated in the draining mediastinal lymph node and the spleen. In addition to immunity within secondary lymphoid organs (SLO), pulmonary infection is also associated with formation of ectopic inducible bronchus-associated tissues (iBALT) in the Lung. These structures display a lymphoid organization, but their function and protective benefits remain unclear. Here we examined the phenotype, transcriptional profile and antigen specificity of B cell populations forming iBALT in influenza infected mice. We show that the cellular composition of iBALT was comparable to SLO, containing populations of follicular dendritic cells (FDC), T-follicular helper (Tfh) cells, and germinal center (GC)-like B cells with classical dark- and light-zone polarization. Transcriptional profiles of GC B cells in iBALT and SLO were conserved regardless of anatomical localization. The architecture of iBALT was pleiomorphic and less structurally defined than SLO. Nevertheless, we show that GC-like structures within iBALT serve as a distinct niche that independently support the maturation and selection of B cells primarily targeted against the influenza virus nucleoprotein. Our findings suggest that iBALT, which are positioned at the frontline of the Lung Mucosa, drive long-lived, and unique GC reactions that contribute to the diversity of the humoral response targeting influenza.
