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1.
N Engl J Med ; 389(25): 2355-2362, 2023 Dec 21.
Artículo en Inglés | MEDLINE | ID: mdl-38118023

RESUMEN

Melioidosis, caused by Burkholderia pseudomallei, is a rare but potentially fatal bacterial disease endemic to tropical and subtropical regions worldwide. It is typically acquired through contact with contaminated soil or fresh water. Before this investigation, B. pseudomallei was not known to have been isolated from the environment in the continental United States. Here, we report on three patients living in the same Mississippi Gulf Coast county who presented with melioidosis within a 3-year period. They were infected by the same Western Hemisphere B. pseudomallei strain that was discovered in three environmental samples collected from the property of one of the patients. These findings indicate local acquisition of melioidosis from the environment in the Mississippi Gulf Coast region.


Asunto(s)
Burkholderia pseudomallei , Microbiología Ambiental , Melioidosis , Humanos , Burkholderia pseudomallei/genética , Burkholderia pseudomallei/aislamiento & purificación , Melioidosis/epidemiología , Melioidosis/microbiología , Estados Unidos/epidemiología
2.
Emerg Infect Dis ; 29(3): 618-621, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36823515

RESUMEN

Burkholderia thailandensis, an opportunistic pathogen found in the environment, is a bacterium closely related to B. pseudomallei, the cause of melioidosis. Human B. thailandensis infections are uncommon. We isolated B. thailandensis from water in Texas and Puerto Rico and soil in Mississippi in the United States, demonstrating a potential public health risk.


Asunto(s)
Infecciones por Burkholderia , Burkholderia pseudomallei , Burkholderia , Melioidosis , Estados Unidos , Humanos , Infecciones por Burkholderia/microbiología
3.
Proc Natl Acad Sci U S A ; 114(49): E10568-E10577, 2017 12 05.
Artículo en Inglés | MEDLINE | ID: mdl-29162686

RESUMEN

Dendritic cells (DCs) are activated by pathogens to initiate and shape immune responses. We found that the activation of DCs by Plasmodium falciparum, the main causative agent of human malaria, induces a highly unusual phenotype by which DCs up-regulate costimulatory molecules and secretion of chemokines, but not of cytokines typical of inflammatory responses (IL-1ß, IL-6, IL-10, TNF). Similar results were obtained with DCs obtained from malaria-naïve US donors and malaria-experienced donors from Mali. Contact-dependent cross-talk between the main DC subsets, plasmacytoid and myeloid DCs (mDCs) was necessary for increased chemokine and IFN-α secretion in response to the parasite. Despite the absence of inflammatory cytokine secretion, mDCs incubated with P. falciparum-infected erythrocytes activated antigen-specific naïve CD4+ T cells to proliferate and secrete Th1-like cytokines. This unexpected response of human mDCs to P. falciparum exhibited a transcriptional program distinct from a classical LPS response, pointing to unique P. falciparum-induced activation pathways that may explain the uncharacteristic immune response to malaria.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Células Dendríticas/inmunología , Eritrocitos/parasitología , Interacciones Huésped-Parásitos , Activación de Linfocitos , Plasmodium falciparum/metabolismo , Antígenos CD/genética , Antígenos CD/inmunología , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/efectos de los fármacos , Quimiocina CCL2/genética , Quimiocina CCL2/inmunología , Quimiocina CCL5/genética , Quimiocina CCL5/inmunología , Quimiocina CXCL10/genética , Quimiocina CXCL10/inmunología , Quimiocina CXCL9/genética , Quimiocina CXCL9/inmunología , Técnicas de Cocultivo , Células Dendríticas/efectos de los fármacos , Células Dendríticas/parasitología , Regulación de la Expresión Génica , Antígenos HLA-DR/genética , Antígenos HLA-DR/inmunología , Humanos , Interleucina-10/genética , Interleucina-10/inmunología , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Lipopolisacáridos/farmacología , Malaria Falciparum/genética , Malaria Falciparum/inmunología , Malaria Falciparum/parasitología , Malí , Plasmodium falciparum/crecimiento & desarrollo , Transducción de Señal , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología
4.
Cell Rep Med ; 3(6): 100640, 2022 06 21.
Artículo en Inglés | MEDLINE | ID: mdl-35588734

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific CD4+ T cells are likely important in immunity against coronavirus 2019 (COVID-19), but our understanding of CD4+ longitudinal dynamics following infection and of specific features that correlate with the maintenance of neutralizing antibodies remains limited. Here, we characterize SARS-CoV-2-specific CD4+ T cells in a longitudinal cohort of 109 COVID-19 outpatients enrolled during acute infection. The quality of the SARS-CoV-2-specific CD4+ response shifts from cells producing interferon gamma (IFNγ) to tumor necrosis factor alpha (TNF-α) from 5 days to 4 months post-enrollment, with IFNγ-IL-21-TNF-α+ CD4+ T cells the predominant population detected at later time points. Greater percentages of IFNγ-IL-21-TNF-α+ CD4+ T cells on day 28 correlate with SARS-CoV-2-neutralizing antibodies measured 7 months post-infection (⍴ = 0.4, p = 0.01). mRNA vaccination following SARS-CoV-2 infection boosts both IFNγ- and TNF-α-producing, spike-protein-specific CD4+ T cells. These data suggest that SARS-CoV-2-specific, TNF-α-producing CD4+ T cells may play an important role in antibody maintenance following COVID-19.


Asunto(s)
COVID-19 , SARS-CoV-2 , Anticuerpos Neutralizantes , Linfocitos T CD4-Positivos , Humanos , Pacientes Ambulatorios , Linfocitos T , Factor de Necrosis Tumoral alfa
5.
Immunohorizons ; 3(11): 511-518, 2019 11 05.
Artículo en Inglés | MEDLINE | ID: mdl-31690559

RESUMEN

Malaria is a highly inflammatory disease caused by the protozoan parasite Plasmodium During the blood stage of infection, patients exhibit fever with high levels of inflammatory cytokines in their blood. However, when cells of the immune system are incubated with the parasite in vitro, their cytokine response is low. In particular, human primary dendritic cells (DCs) respond to Plasmodium falciparum-infected erythrocytes by upregulating maturation markers and chemokines but lack a substantial cytokine response. Because oxidative stress is a trigger of inflammatory cytokines in malaria and synergizes with P. falciparum to induce IL-1ß secretion by macrophages, we assessed whether oxidative stress has an impact on DC maturation and function in response to P. falciparum Using xanthine oxidase, a reactive oxygen species- (ROS) producing enzyme that is increased during malaria, we observed that exposure to extracellular ROS potentiated DC maturation in response to the parasite. Xanthine oxidase-derived ROS increased parasite-induced cytokine secretion and CD80 surface expression in DCs. This enhanced maturation phenotype boosted the DCs' ability to prime autologous naive CD4+ T cells, resulting in higher T cell proliferation in vitro. Xanthine oxidase-derived ROS did not have an effect on the cytokines produced by primed T cells. We propose that oxidative stress during malaria contributes to the inflammatory response by enhancing the magnitude of DC and CD4+ T cell responses without changing the quality.


Asunto(s)
Citocinas/inmunología , Células Dendríticas/inmunología , Eritrocitos/parasitología , Malaria Falciparum/inmunología , Estrés Oxidativo , Linfocitos T CD4-Positivos/inmunología , Células Dendríticas/parasitología , Humanos , Activación de Linfocitos , Plasmodium falciparum
6.
PLoS One ; 14(12): e0225588, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31841511

RESUMEN

Macrophages can reprogram their metabolism in response to the surrounding stimuli, which affects their capacity to kill intracellular pathogens. We have investigated the metabolic and immune status of human macrophages after infection with the intracellular trypanosomatid parasites Leishmania donovani, L. amazonensis and T. cruzi and their capacity to respond to a classical polarizing stimulus (LPS and IFN-γ). We found that macrophages infected with Leishmania preferentially upregulate oxidative phosphorylation, which could be contributed by both host cell and parasite, while T. cruzi infection did not significantly increase glycolysis or oxidative phosphorylation. Leishmania and T. cruzi infect macrophages without triggering a strong inflammatory cytokine response, but infection does not prevent a potent response to LPS and IFN-γ. Infection appears to prime macrophages, since the cytokine response to activation with LPS and IFN-γ is more intense in infected macrophages compared to uninfected ones. Metabolic polarization in macrophages can influence infection and immune evasion of these parasites since preventing macrophage cytokine responses would help parasites to establish a persistent infection. However, macrophages remain responsive to classical inflammatory stimuli and could still trigger inflammatory cytokine secretion by macrophages.


Asunto(s)
Enfermedad de Chagas/inmunología , Citocinas/metabolismo , Leishmaniasis/inmunología , Activación de Macrófagos , Macrófagos/inmunología , Células 3T3 , Animales , Células Cultivadas , Enfermedad de Chagas/sangre , Enfermedad de Chagas/parasitología , Citocinas/inmunología , Voluntarios Sanos , Humanos , Leishmania donovani/inmunología , Leishmania donovani/aislamiento & purificación , Leishmania mexicana/inmunología , Leishmania mexicana/aislamiento & purificación , Leishmaniasis/sangre , Leishmaniasis/parasitología , Macrófagos/metabolismo , Metaboloma/inmunología , Ratones , Fosforilación Oxidativa , Cultivo Primario de Células , Trypanosoma cruzi/inmunología , Trypanosoma cruzi/aislamiento & purificación , Regulación hacia Arriba
7.
EMBO Mol Med ; 11(8): e9903, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31265218

RESUMEN

Malaria is a highly inflammatory disease caused by Plasmodium infection of host erythrocytes. However, the parasite does not induce inflammatory cytokine responses in macrophages in vitro and the source of inflammation in patients remains unclear. Here, we identify oxidative stress, which is common in malaria, as an effective trigger of the inflammatory activation of macrophages. We observed that extracellular reactive oxygen species (ROS) produced by xanthine oxidase (XO), an enzyme upregulated during malaria, induce a strong inflammatory cytokine response in primary human monocyte-derived macrophages. In malaria patients, elevated plasma XO activity correlates with high levels of inflammatory cytokines and with the development of cerebral malaria. We found that incubation of macrophages with plasma from these patients can induce a XO-dependent inflammatory cytokine response, identifying a host factor as a trigger for inflammation in malaria. XO-produced ROS also increase the synthesis of pro-IL-1ß, while the parasite activates caspase-1, providing the two necessary signals for the activation of the NLRP3 inflammasome. We propose that XO-produced ROS are a key factor for the trigger of inflammation during malaria.


Asunto(s)
Inflamación/enzimología , Macrófagos/enzimología , Malaria Cerebral/enzimología , Malaria Falciparum/enzimología , Estrés Oxidativo , Plasmodium falciparum/patogenicidad , Especies Reactivas de Oxígeno/metabolismo , Xantina Oxidasa/metabolismo , Caspasa 1/metabolismo , Células Cultivadas , Citocinas/metabolismo , Interacciones Huésped-Patógeno , Humanos , Inflamación/sangre , Inflamación/parasitología , Mediadores de Inflamación/metabolismo , Activación de Macrófagos , Macrófagos/parasitología , Malaria Cerebral/sangre , Malaria Cerebral/parasitología , Malaria Falciparum/sangre , Malaria Falciparum/parasitología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Transducción de Señal
8.
Front Microbiol ; 9: 482, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29599764

RESUMEN

Bacillus anthracis is an endemic soil bacterium that exhibits two different lifestyles. In the soil environment, B. anthracis undergoes a cycle of saprophytic growth, sporulation, and germination. In mammalian hosts, the pathogenic lifestyle of B. anthracis is spore germination followed by vegetative cell replication, but cells do not sporulate. During infection, and in specific culture conditions, transcription of the structural genes for the anthrax toxin proteins and the biosynthetic operon for capsule synthesis is positively controlled by the regulatory protein AtxA. A critical role for the atxA gene in B. anthracis virulence has been established. Here we report an inverse relationship between toxin production and sporulation that is linked to AtxA levels. During culture in conditions favoring sporulation, B. anthracis produces little to no AtxA. When B. anthracis is cultured in conditions favoring toxin gene expression, AtxA is expressed at relatively high levels and sporulation rate and efficiency are reduced. We found that a mutation within the atxA promoter region resulting in AtxA over-expression leads to a marked sporulation defect. The sporulation phenotype of the mutant is dependent upon pXO2-0075, an atxA-regulated open reading frame located on virulence plasmid pXO2. The predicted amino acid sequence of the pXO2-0075 protein has similarity to the sensor domain of sporulation sensor histidine kinases. It was shown previously that pXO2-0075 overexpression suppresses sporulation. We have designated pXO2-0075 "skiA" for "sporulation kinase inhibitor." Our results indicate that in addition to serving as a positive regulator of virulence gene expression, AtxA modulates B. anthracis development.

9.
PLoS One ; 10(9): e0138191, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26376293

RESUMEN

Angiotensin II, a peptide hormone that regulates blood pressure, has been proposed as a protective factor against cerebral malaria based on a genetic analysis. In vitro studies have documented an inhibitory effect of angiotensin II on Plasmodium growth, while studies using chemical inhibitors of angiotensin II in mice showed protection against experimental cerebral malaria but not major effects on parasite growth. To determine whether the level of angiotensin II affects Plasmodium growth and/or disease outcome in malaria, elevated levels of angiotensin II were induced in mice by intradermal implantation of osmotic mini-pumps providing constant release of this hormone. Mice were then infected with P. berghei and monitored for parasitemia and incidence of cerebral malaria. Mice infused with angiotensin II showed decreased parasitemia seven days after infection. The development of experimental cerebral malaria was delayed and a moderate increase in survival was observed in mice with elevated angiotensin II, as confirmed by decreased number of cerebral hemorrhages compared to controls. The results presented here show for the first time the effect of elevated levels of angiotensin II in an in vivo model of malaria. The decreased pathogenesis observed in mice complements a previous human genetic study, reinforcing the hypothesis of a beneficial effect of angiotensin II in malaria.


Asunto(s)
Angiotensina II/farmacología , Modelos Animales de Enfermedad , Malaria Cerebral/prevención & control , Malaria/prevención & control , Parasitemia/prevención & control , Plasmodium berghei/fisiología , Animales , Humanos , Malaria/sangre , Malaria/parasitología , Malaria Cerebral/sangre , Malaria Cerebral/parasitología , Ratones , Ratones Endogámicos C57BL , Parasitemia/sangre , Parasitemia/parasitología , Vasoconstrictores/farmacología
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