Ellen Quarles | University of Washington (original) (raw)

Papers by Ellen Quarles

Research paper thumbnail of Polyphosphate Functions In Vivo as an Iron Chelator and Fenton Reaction Inhibitor

mBio

Maintaining cellular iron homeostasis is critical for organismal survival. Whereas iron depletion... more Maintaining cellular iron homeostasis is critical for organismal survival. Whereas iron depletion negatively affects the many metabolic pathways that depend on the activity of iron-containing enzymes, any excess of iron can cause the rapid formation of highly toxic reactive oxygen species (ROS) through Fenton chemistry. Although several cellular iron chelators have been identified, little is known about if and how organisms can prevent the Fenton reaction. By studying the effects of cisplatin, a commonly used anticancer drug and effective antimicrobial, we discovered that cisplatin elicits severe iron stress and oxidative DNA damage in bacteria. We found that both of these effects are successfully prevented by polyphosphate (polyP), an abundant polymer consisting solely of covalently linked inorganic phosphates. Subsequent in vitro and in vivo studies revealed that polyP provides a crucial iron reservoir under nonstress conditions and effectively complexes free iron and blocks ROS f...

Research paper thumbnail of Automated phenotyping and lifespan assessment of a C. elegans model of Parkinson's disease

Translational Medicine of Aging

Research paper thumbnail of Transient and late-life rapamycin for healthspan extension

Research paper thumbnail of Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice

Mitochondrial dysfunction is a hallmark of aging but whether restoration of mitochondrial functio... more Mitochondrial dysfunction is a hallmark of aging but whether restoration of mitochondrial function can reverse pre-existing age-related diseases is not well-established. Diastolic dysfunction is a prominent feature of cardiac aging in both mice and humans, and we show here that 8-week treatment with the mitochondrial targeted peptide SS-31 (elamipretide) can substantially reverse this deficit in old mice. Mechanistically, SS-31 treatment normalized the increase in proton leak and reduced mitochondrial ROS in cardiomyocytes from old mice; these cellular changes were accompanied by reduced protein oxidation and a shift towards a more reduced protein thiol redox state in old hearts. The improvement in diastolic function was associated with increased phosphorylation at Ser282 of cMyBP-C but was independent of titin isoform shift. SS-31 treatment cannot further improve cardiac function of old mice that express mitochondrial-targeted catalase (mCAT), implicating normalizing mitochondrial ...

Research paper thumbnail of Polyphosphate Functions In Vivo as Iron Chelator and Fenton Inhibitor

Maintaining cellular iron homeostasis is critical for organismal survival. Whereas iron depletion... more Maintaining cellular iron homeostasis is critical for organismal survival. Whereas iron depletion negatively affects the many metabolic pathways that depend on the activity of iron-containing enzymes, any excess of iron can cause the rapid formation of highly toxic reactive oxygen species (ROS) through Fenton chemistry. Although several cellular iron chelators have been identified, little is known about if and how organisms can prevent the Fenton reaction. By studying the effects of cisplatin, a commonly used anticancer drug and effective antimicrobial, we discovered that cisplatin elicits severe iron stress and oxidative DNA damage in bacteria. We found that both of these effects are successfully prevented by polyphosphate (polyP), an abundant polymer consisting solely of covalently linked inorganic phosphates. Subsequent in vitro and in vivo studies revealed that polyP provides a crucial iron reservoir under non-stress conditions, and effectively complexes free iron and blocks ROS...

Research paper thumbnail of Salmonella evasion of a caspase-1 dependent mucosal barrier

Salmonella enterica Typhimurium is a flagellated bacterium and one of the leading causes of gastr... more Salmonella enterica Typhimurium is a flagellated bacterium and one of the leading causes of gastroenteritis in humans. Bacterial flagellin is critical for motility and also a prime target of the innate immune system. Innate immune recognition of flagellin is mediated by two independent innate immune pathways, TLR5 and Naip5-Naip6/NlrC4/Caspase-1. The functional significance of each of the two independent flagellin recognition systems in innate immunity to Salmonella infection is modest, and we hypothesized that this was due to efficient modulation of flagellin expression in vivo to evade innate immune detection. Salmonella deficient in the anti-sigma factor flgM overexpress flagellin, are attenuated in vivo, and this attenuation is dependent on flagellin expression. In this study, we used flgM- Salmonella to determine if flagellin recognition by the innate immune system was responsible for the attenuation of flgM- S. typhimurium, and to dissect the contribution of each flagellin rec...

Research paper thumbnail of Melorheostosis of the index finger: a case report

Radiology Case Reports, 2008

Research paper thumbnail of Regulation of antibody responses to flagellin by the innate immune system

Flagellin is the predominant component of the bacterial flagellum. It is exposed on the surface o... more Flagellin is the predominant component of the bacterial flagellum. It is exposed on the surface of bacteria and is a major target of host immune responses. Flagellin has four domains: D0, D1, D2 and D3. The conserved D0 and D1 domains of flagellin are recognized by the innate immune system through multiple pathways, including TLR5, which recognizes the D1 domain, and Naip5/6, which recognizes the carboxyl end of the D0 domain. Preliminary data indicates that antibody responses are regulated by components of the innate immune system that confer flagellin recognition. IgG2c antibody responses in mice are dependent on MyD88, while IgG1 responses are independent of MyD88. We hypothesize that the conserved structural features of flagellin regulate these responses, and that TLR5 and Naip5/6 are the innate recognition pathways that determine Myd88-dependent IgG2c production. My project aims are: 1) define the structural components of flagellin that determine antibody responses and 2) deter...

Research paper thumbnail of Subacute calorie restriction and rapamycin discordantly alter mouse liver proteome homeostasis and reverse aging effects

Aging cell, Jan 23, 2015

Calorie restriction (CR) and rapamycin (RP) extend lifespan and improve health across model organ... more Calorie restriction (CR) and rapamycin (RP) extend lifespan and improve health across model organisms. Both treatments inhibit mammalian target of rapamycin (mTOR) signaling, a conserved longevity pathway and a key regulator of protein homeostasis, yet their effects on proteome homeostasis are relatively unknown. To comprehensively study the effects of aging, CR, and RP on protein homeostasis, we performed the first simultaneous measurement of mRNA translation, protein turnover, and abundance in livers of young (3 month) and old (25 month) mice subjected to 10-week RP or 40% CR. Protein abundance and turnover were measured in vivo using (2) H3 -leucine heavy isotope labeling followed by LC-MS/MS, and translation was assessed by polysome profiling. We observed 35-60% increased protein half-lives after CR and 15% increased half-lives after RP compared to age-matched controls. Surprisingly, the effects of RP and CR on protein turnover and abundance differed greatly between canonical pa...

Research paper thumbnail of Quality Control Systems in Cardiac Aging

Ageing Research Reviews, 2015

Cardiac aging is an intrinsic process that results in impaired cardiac function, along with cellu... more Cardiac aging is an intrinsic process that results in impaired cardiac function, along with cellular and molecular changes. These degenerative changes are intimately associated with quality control mechanisms. This review provides a general overview of the clinical and cellular changes which manifest in cardiac aging, and the quality control mechanisms involved in maintaining homeostasis and retarding aging. These mechanisms include autophagy, ubiquitin-mediated turnover, apoptosis, mitochondrial quality control and cardiac matrix homeostasis. Finally, we discuss aging interventions that have been observed to impact cardiac health outcomes. These include caloric restriction, rapamycin, resveratrol, GDF11, mitochondrial antioxidants and cardiolipin-targeted therapeutics. A greater understanding of the quality control mechanisms that promote cardiac homeostasis will help to understand the benefits of these interventions, and hopefully lead to further improved therapeutic modalities.

Research paper thumbnail of Innate Immune Detection of Flagellin Positively and Negatively Regulates Salmonella Infection

PLoS ONE, 2013

Salmonella enterica serovar Typhimurium is a flagellated bacterium and one of the leading causes ... more Salmonella enterica serovar Typhimurium is a flagellated bacterium and one of the leading causes of gastroenteritis in humans. Bacterial flagellin is required for motility and also a prime target of the innate immune system. Innate immune recognition of flagellin is mediated by at least two independent pathways, TLR5 and Naip5-Naip6/NlrC4/Caspase-1. The functional significance of each of the two independent flagellin recognition systems for host defense against wild type Salmonella infection is complex, and innate immune detection of flagellin contributes to both protection and susceptibility. We hypothesized that efficient modulation of flagellin expression in vivo permits Salmonella to evade innate immune detection and limit the functional role of flagellin-specific host innate defenses. To test this hypothesis, we used Salmonella deficient in the anti-sigma factor flgM, which overproduce flagella and are attenuated in vivo. In this study we demonstrate that flagellin recognition by the innate immune system is responsible for the attenuation of flgM 2 S. Typhimurium, and dissect the contribution of each flagellin recognition pathway to bacterial clearance and inflammation. We demonstrate that caspase-1 controls mucosal and systemic infection of flgM 2 S. Typhimurium, and also limits intestinal inflammation and injury. In contrast, TLR5 paradoxically promotes bacterial colonization in the cecum and systemic infection, but attenuates intestinal inflammation. Our results indicate that Salmonella evasion of caspase-1 dependent flagellin recognition is critical for establishing infection and that evasion of TLR5 and caspase-1 dependent flagellin recognition helps Salmonella induce intestinal inflammation and establish a niche in the inflamed gut.

Research paper thumbnail of Flagellin Induces Antibody Responses through a TLR5- and Inflammasome-Independent Pathway

The Journal of Immunology, 2014

Flagellin is a potent immunogen that activates the innate immune system via TLR5 and Naip5/6, and... more Flagellin is a potent immunogen that activates the innate immune system via TLR5 and Naip5/6, and generates strong T and B cell responses. The adaptor protein MyD88 is critical for signaling by TLR5, as well as IL-1Rs and IL-18Rs, major downstream mediators of the Naip5/6 Nlrc4-inflammasome. In this study, we define roles of known flagellin receptors and MyD88 in Ab responses generated toward flagellin. We used mice genetically deficient in flagellin recognition pathways to characterize innate immune components that regulate isotype-specific Ab responses. Using purified flagellin from Salmonella, we dissected the contribution of innate flagellin recognition pathways to promote Ab responses toward flagellin and coadministered OVA in C57BL/6 mice. We demonstrate IgG2c responses toward flagellin were TLR5 and inflammasome dependent; IgG1 was the dominant isotype and partially TLR5 and inflammasome dependent. Our data indicate a substantial flagellin-specific IgG1 response was induced through a TLR5-, inflammasome-, and MyD88-independent pathway. IgA anti-FliC responses were TLR5 and MyD88 dependent and caspase-1 independent. Unlike C57BL/6 mice, flagellin-immunized A/J mice induced codominant IgG1 and IgG2a responses. Furthermore, MyD88-independent, flagellin-induced Ab responses were even more pronounced in A/J MyD88(-/-) mice, and IgA anti-FliC responses were suppressed by MyD88. Flagellin also worked as an adjuvant toward coadministered OVA, but it only promoted IgG1 anti-OVA responses. Our results demonstrate that a novel pathway for flagellin recognition contributes to Ab production. Characterization of this pathway will be useful for understanding immunity to flagellin and the rationale design of flagellin-based vaccines.

Research paper thumbnail of The Innate Immune Response to Salmonella enterica Serovar Typhimurium by Macrophages Is Dependent on TREM2-DAP12

Infection and Immunity, 2008

Macrophage recognition of Salmonella enterica serovar Typhimurium leads to a cascade of signaling... more Macrophage recognition of Salmonella enterica serovar Typhimurium leads to a cascade of signaling events, including the activation of Src family and Syk kinases and the production of reactive oxygen species (ROS), which are critical for host innate defense during early stages of bacterial infection. ROS production depends on the NADPH oxidase, but little is known about the innate immune receptors and proximal adapters that regulate Salmonella-induced ROS. Herein, we demonstrate that serovar Typhimurium induces ROS through a pathway that requires both triggering receptor expressed on myeloid cells 2 (TREM2) and DAP12. This pathway is highly analogous to the pathways utilized by Fc receptors and integrins to regulate ROS production. Oral infection of mice with serovar Typhimurium demonstrates that the DAP12-dependent pathway regulates cecal colonization during early stages of Salmonella infection. Thus, DAP12 is an important regulator of Salmonella-induced ROS production in macrophages, and TREM2 is essential for linking DAP12 to the innate response to serovar Typhimurium.

Research paper thumbnail of Mitochondrial dysfunction in cardiac aging

Biochimica et Biophysica Acta (BBA) - Bioenergetics, 2015

Cardiovascular diseases are the leading cause of death in most developed nations. While it has re... more Cardiovascular diseases are the leading cause of death in most developed nations. While it has received the least public attention, aging is the dominant risk factor for developing cardiovascular diseases, as the prevalence of cardiovascular diseases increases dramatically with increasing age. Cardiac aging is an intrinsic process that results in impaired cardiac function, along with cellular and molecular changes. Mitochondria play a great role in these processes, as cardiac function is an energetically demanding process. In this review, we examine mitochondrial dysfunction in cardiac aging. Recent research has demonstrated that mitochondrial dysfunction can disrupt morphology, signaling pathways, and protein interactions; conversely, mitochondrial homeostasis is maintained by mechanisms that include fission/fusion, autophagy, and unfolded protein responses. Finally, we describe some of the recent findings in mitochondrial targeted treatments to help meet the challenges of mitochondrial dysfunction in aging.

Research paper thumbnail of Polyphosphate Functions In Vivo as an Iron Chelator and Fenton Reaction Inhibitor

mBio

Maintaining cellular iron homeostasis is critical for organismal survival. Whereas iron depletion... more Maintaining cellular iron homeostasis is critical for organismal survival. Whereas iron depletion negatively affects the many metabolic pathways that depend on the activity of iron-containing enzymes, any excess of iron can cause the rapid formation of highly toxic reactive oxygen species (ROS) through Fenton chemistry. Although several cellular iron chelators have been identified, little is known about if and how organisms can prevent the Fenton reaction. By studying the effects of cisplatin, a commonly used anticancer drug and effective antimicrobial, we discovered that cisplatin elicits severe iron stress and oxidative DNA damage in bacteria. We found that both of these effects are successfully prevented by polyphosphate (polyP), an abundant polymer consisting solely of covalently linked inorganic phosphates. Subsequent in vitro and in vivo studies revealed that polyP provides a crucial iron reservoir under nonstress conditions and effectively complexes free iron and blocks ROS f...

Research paper thumbnail of Automated phenotyping and lifespan assessment of a C. elegans model of Parkinson's disease

Translational Medicine of Aging

Research paper thumbnail of Transient and late-life rapamycin for healthspan extension

Research paper thumbnail of Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice

Mitochondrial dysfunction is a hallmark of aging but whether restoration of mitochondrial functio... more Mitochondrial dysfunction is a hallmark of aging but whether restoration of mitochondrial function can reverse pre-existing age-related diseases is not well-established. Diastolic dysfunction is a prominent feature of cardiac aging in both mice and humans, and we show here that 8-week treatment with the mitochondrial targeted peptide SS-31 (elamipretide) can substantially reverse this deficit in old mice. Mechanistically, SS-31 treatment normalized the increase in proton leak and reduced mitochondrial ROS in cardiomyocytes from old mice; these cellular changes were accompanied by reduced protein oxidation and a shift towards a more reduced protein thiol redox state in old hearts. The improvement in diastolic function was associated with increased phosphorylation at Ser282 of cMyBP-C but was independent of titin isoform shift. SS-31 treatment cannot further improve cardiac function of old mice that express mitochondrial-targeted catalase (mCAT), implicating normalizing mitochondrial ...

Research paper thumbnail of Polyphosphate Functions In Vivo as Iron Chelator and Fenton Inhibitor

Maintaining cellular iron homeostasis is critical for organismal survival. Whereas iron depletion... more Maintaining cellular iron homeostasis is critical for organismal survival. Whereas iron depletion negatively affects the many metabolic pathways that depend on the activity of iron-containing enzymes, any excess of iron can cause the rapid formation of highly toxic reactive oxygen species (ROS) through Fenton chemistry. Although several cellular iron chelators have been identified, little is known about if and how organisms can prevent the Fenton reaction. By studying the effects of cisplatin, a commonly used anticancer drug and effective antimicrobial, we discovered that cisplatin elicits severe iron stress and oxidative DNA damage in bacteria. We found that both of these effects are successfully prevented by polyphosphate (polyP), an abundant polymer consisting solely of covalently linked inorganic phosphates. Subsequent in vitro and in vivo studies revealed that polyP provides a crucial iron reservoir under non-stress conditions, and effectively complexes free iron and blocks ROS...

Research paper thumbnail of Salmonella evasion of a caspase-1 dependent mucosal barrier

Salmonella enterica Typhimurium is a flagellated bacterium and one of the leading causes of gastr... more Salmonella enterica Typhimurium is a flagellated bacterium and one of the leading causes of gastroenteritis in humans. Bacterial flagellin is critical for motility and also a prime target of the innate immune system. Innate immune recognition of flagellin is mediated by two independent innate immune pathways, TLR5 and Naip5-Naip6/NlrC4/Caspase-1. The functional significance of each of the two independent flagellin recognition systems in innate immunity to Salmonella infection is modest, and we hypothesized that this was due to efficient modulation of flagellin expression in vivo to evade innate immune detection. Salmonella deficient in the anti-sigma factor flgM overexpress flagellin, are attenuated in vivo, and this attenuation is dependent on flagellin expression. In this study, we used flgM- Salmonella to determine if flagellin recognition by the innate immune system was responsible for the attenuation of flgM- S. typhimurium, and to dissect the contribution of each flagellin rec...

Research paper thumbnail of Melorheostosis of the index finger: a case report

Radiology Case Reports, 2008

Research paper thumbnail of Regulation of antibody responses to flagellin by the innate immune system

Flagellin is the predominant component of the bacterial flagellum. It is exposed on the surface o... more Flagellin is the predominant component of the bacterial flagellum. It is exposed on the surface of bacteria and is a major target of host immune responses. Flagellin has four domains: D0, D1, D2 and D3. The conserved D0 and D1 domains of flagellin are recognized by the innate immune system through multiple pathways, including TLR5, which recognizes the D1 domain, and Naip5/6, which recognizes the carboxyl end of the D0 domain. Preliminary data indicates that antibody responses are regulated by components of the innate immune system that confer flagellin recognition. IgG2c antibody responses in mice are dependent on MyD88, while IgG1 responses are independent of MyD88. We hypothesize that the conserved structural features of flagellin regulate these responses, and that TLR5 and Naip5/6 are the innate recognition pathways that determine Myd88-dependent IgG2c production. My project aims are: 1) define the structural components of flagellin that determine antibody responses and 2) deter...

Research paper thumbnail of Subacute calorie restriction and rapamycin discordantly alter mouse liver proteome homeostasis and reverse aging effects

Aging cell, Jan 23, 2015

Calorie restriction (CR) and rapamycin (RP) extend lifespan and improve health across model organ... more Calorie restriction (CR) and rapamycin (RP) extend lifespan and improve health across model organisms. Both treatments inhibit mammalian target of rapamycin (mTOR) signaling, a conserved longevity pathway and a key regulator of protein homeostasis, yet their effects on proteome homeostasis are relatively unknown. To comprehensively study the effects of aging, CR, and RP on protein homeostasis, we performed the first simultaneous measurement of mRNA translation, protein turnover, and abundance in livers of young (3 month) and old (25 month) mice subjected to 10-week RP or 40% CR. Protein abundance and turnover were measured in vivo using (2) H3 -leucine heavy isotope labeling followed by LC-MS/MS, and translation was assessed by polysome profiling. We observed 35-60% increased protein half-lives after CR and 15% increased half-lives after RP compared to age-matched controls. Surprisingly, the effects of RP and CR on protein turnover and abundance differed greatly between canonical pa...

Research paper thumbnail of Quality Control Systems in Cardiac Aging

Ageing Research Reviews, 2015

Cardiac aging is an intrinsic process that results in impaired cardiac function, along with cellu... more Cardiac aging is an intrinsic process that results in impaired cardiac function, along with cellular and molecular changes. These degenerative changes are intimately associated with quality control mechanisms. This review provides a general overview of the clinical and cellular changes which manifest in cardiac aging, and the quality control mechanisms involved in maintaining homeostasis and retarding aging. These mechanisms include autophagy, ubiquitin-mediated turnover, apoptosis, mitochondrial quality control and cardiac matrix homeostasis. Finally, we discuss aging interventions that have been observed to impact cardiac health outcomes. These include caloric restriction, rapamycin, resveratrol, GDF11, mitochondrial antioxidants and cardiolipin-targeted therapeutics. A greater understanding of the quality control mechanisms that promote cardiac homeostasis will help to understand the benefits of these interventions, and hopefully lead to further improved therapeutic modalities.

Research paper thumbnail of Innate Immune Detection of Flagellin Positively and Negatively Regulates Salmonella Infection

PLoS ONE, 2013

Salmonella enterica serovar Typhimurium is a flagellated bacterium and one of the leading causes ... more Salmonella enterica serovar Typhimurium is a flagellated bacterium and one of the leading causes of gastroenteritis in humans. Bacterial flagellin is required for motility and also a prime target of the innate immune system. Innate immune recognition of flagellin is mediated by at least two independent pathways, TLR5 and Naip5-Naip6/NlrC4/Caspase-1. The functional significance of each of the two independent flagellin recognition systems for host defense against wild type Salmonella infection is complex, and innate immune detection of flagellin contributes to both protection and susceptibility. We hypothesized that efficient modulation of flagellin expression in vivo permits Salmonella to evade innate immune detection and limit the functional role of flagellin-specific host innate defenses. To test this hypothesis, we used Salmonella deficient in the anti-sigma factor flgM, which overproduce flagella and are attenuated in vivo. In this study we demonstrate that flagellin recognition by the innate immune system is responsible for the attenuation of flgM 2 S. Typhimurium, and dissect the contribution of each flagellin recognition pathway to bacterial clearance and inflammation. We demonstrate that caspase-1 controls mucosal and systemic infection of flgM 2 S. Typhimurium, and also limits intestinal inflammation and injury. In contrast, TLR5 paradoxically promotes bacterial colonization in the cecum and systemic infection, but attenuates intestinal inflammation. Our results indicate that Salmonella evasion of caspase-1 dependent flagellin recognition is critical for establishing infection and that evasion of TLR5 and caspase-1 dependent flagellin recognition helps Salmonella induce intestinal inflammation and establish a niche in the inflamed gut.

Research paper thumbnail of Flagellin Induces Antibody Responses through a TLR5- and Inflammasome-Independent Pathway

The Journal of Immunology, 2014

Flagellin is a potent immunogen that activates the innate immune system via TLR5 and Naip5/6, and... more Flagellin is a potent immunogen that activates the innate immune system via TLR5 and Naip5/6, and generates strong T and B cell responses. The adaptor protein MyD88 is critical for signaling by TLR5, as well as IL-1Rs and IL-18Rs, major downstream mediators of the Naip5/6 Nlrc4-inflammasome. In this study, we define roles of known flagellin receptors and MyD88 in Ab responses generated toward flagellin. We used mice genetically deficient in flagellin recognition pathways to characterize innate immune components that regulate isotype-specific Ab responses. Using purified flagellin from Salmonella, we dissected the contribution of innate flagellin recognition pathways to promote Ab responses toward flagellin and coadministered OVA in C57BL/6 mice. We demonstrate IgG2c responses toward flagellin were TLR5 and inflammasome dependent; IgG1 was the dominant isotype and partially TLR5 and inflammasome dependent. Our data indicate a substantial flagellin-specific IgG1 response was induced through a TLR5-, inflammasome-, and MyD88-independent pathway. IgA anti-FliC responses were TLR5 and MyD88 dependent and caspase-1 independent. Unlike C57BL/6 mice, flagellin-immunized A/J mice induced codominant IgG1 and IgG2a responses. Furthermore, MyD88-independent, flagellin-induced Ab responses were even more pronounced in A/J MyD88(-/-) mice, and IgA anti-FliC responses were suppressed by MyD88. Flagellin also worked as an adjuvant toward coadministered OVA, but it only promoted IgG1 anti-OVA responses. Our results demonstrate that a novel pathway for flagellin recognition contributes to Ab production. Characterization of this pathway will be useful for understanding immunity to flagellin and the rationale design of flagellin-based vaccines.

Research paper thumbnail of The Innate Immune Response to Salmonella enterica Serovar Typhimurium by Macrophages Is Dependent on TREM2-DAP12

Infection and Immunity, 2008

Macrophage recognition of Salmonella enterica serovar Typhimurium leads to a cascade of signaling... more Macrophage recognition of Salmonella enterica serovar Typhimurium leads to a cascade of signaling events, including the activation of Src family and Syk kinases and the production of reactive oxygen species (ROS), which are critical for host innate defense during early stages of bacterial infection. ROS production depends on the NADPH oxidase, but little is known about the innate immune receptors and proximal adapters that regulate Salmonella-induced ROS. Herein, we demonstrate that serovar Typhimurium induces ROS through a pathway that requires both triggering receptor expressed on myeloid cells 2 (TREM2) and DAP12. This pathway is highly analogous to the pathways utilized by Fc receptors and integrins to regulate ROS production. Oral infection of mice with serovar Typhimurium demonstrates that the DAP12-dependent pathway regulates cecal colonization during early stages of Salmonella infection. Thus, DAP12 is an important regulator of Salmonella-induced ROS production in macrophages, and TREM2 is essential for linking DAP12 to the innate response to serovar Typhimurium.

Research paper thumbnail of Mitochondrial dysfunction in cardiac aging

Biochimica et Biophysica Acta (BBA) - Bioenergetics, 2015

Cardiovascular diseases are the leading cause of death in most developed nations. While it has re... more Cardiovascular diseases are the leading cause of death in most developed nations. While it has received the least public attention, aging is the dominant risk factor for developing cardiovascular diseases, as the prevalence of cardiovascular diseases increases dramatically with increasing age. Cardiac aging is an intrinsic process that results in impaired cardiac function, along with cellular and molecular changes. Mitochondria play a great role in these processes, as cardiac function is an energetically demanding process. In this review, we examine mitochondrial dysfunction in cardiac aging. Recent research has demonstrated that mitochondrial dysfunction can disrupt morphology, signaling pathways, and protein interactions; conversely, mitochondrial homeostasis is maintained by mechanisms that include fission/fusion, autophagy, and unfolded protein responses. Finally, we describe some of the recent findings in mitochondrial targeted treatments to help meet the challenges of mitochondrial dysfunction in aging.