Essential genes of the macrophage response to Staphylococcus aureus exposure

Sun, Aixia; Zhang, Hongwei; Pang, Feng; Niu, Guifen; Chen, Jianzhong; Chen, Fei; Zhang, Jian

doi:10.1186/s11658-018-0090-4

Cited by 8 publications

(7 citation statements)

References 29 publications

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“…For example, patients with persistent SAB showed hypomethylation of the STAT1 promoter that activates the Th1 pathway, but suppresses Th17 activation. Concordantly, other studies have shown that S. aureus activates human macrophages via STAT1 ( Sun et al., 2018 ). In this scenario, greater IFNγ response would be anticipated to promote macrophage function, but reduced IL-17 would be anticipated to limit neutrophil function.…”

Section: Human Genetic Variability Correlates In S Aureus ...supporting

confidence: 67%

Staphylococcus aureus adaptive evolution: Recent insights on how immune evasion, immunometabolic subversion and host genetics impact vaccine development

Lung

Chan

Prince

et al. 2022

Front. Cell. Infect. Microbiol.

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Despite meritorious attempts, a S. aureus vaccine that prevents infection or mitigates severity has not yet achieved efficacy endpoints in prospective, randomized clinical trials. This experience underscores the complexity of host-S. aureus interactions, which appear to be greater than many other bacterial pathogens against which successful vaccines have been developed. It is increasingly evident that S. aureus employs strategic countermeasures to evade or exploit human immune responses. From entering host cells to persist in stealthy intracellular reservoirs, to sensing the environmental milieu and leveraging bacterial or host metabolic products to reprogram host immune responses, S. aureus poses considerable challenges for the development of effective vaccines. The fact that this pathogen causes distinct types of infections and can undergo transient genetic, transcriptional or metabolic adaptations in vivo that do not occur in vitro compounds challenges in vaccine development. Notably, the metabolic versatility of both bacterial and host immune cells as they compete for available substrates within specific tissues inevitably impacts the variable repertoire of gene products that may or may not be vaccine antigens. In this respect, S. aureus has chameleon phenotypes that have alluded vaccine strategies thus far. Nonetheless, a number of recent studies have also revealed important new insights into pathogenesis vulnerabilities of S. aureus. A more detailed understanding of host protective immune defenses versus S. aureus adaptive immune evasion mechanisms may offer breakthroughs in the development of effective vaccines, but at present this goal remains a very high bar. Coupled with the recent advances in human genetics and epigenetics, newer vaccine technologies may enable such a goal. If so, future vaccines that protect against or mitigate the severity of S. aureus infections are likely to emerge at the intersection of precision and personalized medicine. For now, the development of S. aureus vaccines or alternative therapies that reduce mortality and morbidity must continue to be pursued.

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Section: Human Genetic Variability Correlates In S Aureus ...supporting

confidence: 67%

Staphylococcus aureus adaptive evolution: Recent insights on how immune evasion, immunometabolic subversion and host genetics impact vaccine development

Lung

Chan

Prince

et al. 2022

Front. Cell. Infect. Microbiol.

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“…We identified a SNP that was associated with decreased expression of PRKCA and thus was less able to mediate the IL-17 immune response during Cryptosporidium infection. PRKCA has also been shown to be associated with numerous other infections, including infections by Staphylococcus aureus (26); with progression of sepsis (27) and toxoplasmosis (28); with Burkholderia cenocepacia infections in cystic fibrosis patients (29); and with hepatitis E virus replication (30).…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Association Study of Cryptosporidiosis in Infants Implicates PRKCA

Wojcik

Korpe

Marie

et al. 2020

mBio

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Diarrhea is a major cause of both morbidity and mortality worldwide, especially among young children. Cryptosporidiosis is a leading cause of diarrhea in children, particularly in South Asia and sub-Saharan Africa, where it is responsible for over 200,000 deaths per year. Beyond the initial clinical presentation of diarrhea, it is associated with long-term sequelae such as malnutrition and neurocognitive developmental deficits. Risk factors include poverty and overcrowding, and yet not all children with these risk factors and exposure are infected, nor do all infected children develop symptomatic disease. One potential risk factor to explain these differences is their human genome. To identify genetic variants associated with symptomatic cryptosporidiosis, we conducted a genome-wide association study (GWAS) examining 6.5 million single nucleotide polymorphisms (SNPs) in 873 children from three independent cohorts in Dhaka, Bangladesh, namely, the Dhaka Birth Cohort (DBC), the Performance of Rotavirus and Oral Polio Vaccines in Developing Countries (PROVIDE) study, and the Cryptosporidiosis Birth Cohort (CBC). Associations were estimated separately for each cohort under an additive model, adjusting for length-for-age Z-score at 12 months of age, the first two principal components to account for population substructure, and genotyping batch. The strongest meta-analytic association was with rs58296998 (P = 3.73 × 10−8), an intronic SNP and expression quantitative trait locus (eQTL) of protein kinase C alpha (PRKCA). Each additional risk allele conferred 2.4 times the odds of Cryptosporidium-associated diarrhea in the first year of life. This genetic association suggests a role for protein kinase C alpha in pediatric cryptosporidiosis and warrants further investigation. IMPORTANCE Globally, diarrhea remains one of the major causes of pediatric morbidity and mortality. The initial symptoms of diarrhea can often lead to long-term consequences for the health of young children, such as malnutrition and neurocognitive developmental deficits. Despite many children having similar exposures to infectious causes of diarrhea, not all develop symptomatic disease, indicating a possible role for human genetic variation. Here, we conducted a genetic study of susceptibility to symptomatic disease associated with Cryptosporidium infection (a leading cause of diarrhea) in three independent cohorts of infants from Dhaka, Bangladesh. We identified a genetic variant within protein kinase C alpha (PRKCA) associated with higher risk of cryptosporidiosis in the first year of life. These results indicate a role for human genetics in susceptibility to cryptosporidiosis and warrant further research to elucidate the mechanism.

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“…Some researchers also showed that JAK2/STAT participates in immune responses in activated macrophages induced by Staphylococcus aureus and LPS [ 40 , 41 ]. Our data also implied that the JAK2-specific inhibitor, AG490 (50 μ g/mL), downregulated expression levels of proinflammatory factors TNF- α and IL-6 in macrophages treated with P. gingivalis ( Figure 1 ).…”

Section: Discussionmentioning

confidence: 99%

Coniferyl Aldehyde Inhibits the Inflammatory Effects of Leptomeningeal Cells by Suppressing the JAK2 Signaling

Wang

Gao

et al. 2020

BioMed Research International

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Background. The brain is in many ways an immunologically and pharmacologically privileged site because of the blood-brain barrier (BBB). But for chronic peripheral inflammation, inflammatory signals can be transmitted from the peripheral system into the central nervous system (CNS) through multiple channels and result in neuroinflammation. Leptomeningeal cells that form the BBB can trigger one signaling pathway by releasing cytokines to transmit inflammatory signals. Besides, the Janus kinase (JAK) family may have a certain function in the activation of leptomeninges. In the present study, we try to use coniferyl aldehyde (CA), a natural anti-inflammatory phenolic compound, to inhibit this inflammatory process and elucidate the underlying molecular mechanisms. Results. Secretion of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) significantly increased after incubation with P. gingivalis. Moreover, TNF-α, IL-1β, and IL-6 levels were upregulated, and the JAK2 signaling was enhanced in leptomeningeal cells in a conditioned medium from activated macrophages, which leads to the immune response in microglia. However, this inflammatory effect of leptomeningeal cells was reversed by CA administration, accompanied by the decreased immune response in microglia. The western blot assay revealed that JAK2 phosphorylation was suppressed in leptomeningeal cells treated with CA. Conclusions. This study demonstrates that activated macrophages by P. gingivalis markedly induce the release of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) from leptomeningeal cells, thereby activating the JAK2 signaling pathway and subsequently enhancing immune responses in microglia in the CNS. CA effectively inhibits the inflammatory effect of leptomeningeal cells via suppressing the JAK2 signaling pathway.

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Essential genes of the macrophage response to Staphylococcus aureus exposure

Cited by 8 publications

References 29 publications

Staphylococcus aureus adaptive evolution: Recent insights on how immune evasion, immunometabolic subversion and host genetics impact vaccine development

Staphylococcus aureus adaptive evolution: Recent insights on how immune evasion, immunometabolic subversion and host genetics impact vaccine development

Genome-Wide Association Study of Cryptosporidiosis in Infants Implicates PRKCA

Coniferyl Aldehyde Inhibits the Inflammatory Effects of Leptomeningeal Cells by Suppressing the JAK2 Signaling

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