N-acetylglucosamine (GlcNAc-inducible gene GIG2 is a novel component of GlcNAc metabolism in Candida albicans

Candida albicans is an opportunistic fungal pathogen that resides in the human body as a commensal and can turn pathogenic when the host is immunocompromised. Adaptation of C. albicans to host niche-specific conditions is important for the establishment of pathogenicity, where the ability of C. albicans to utilize multiple carbon sources provides additional flexibility. One alternative sugar is N-acetylglucosamine (GlcNAc), which is now established as an important carbon source for many pathogens and can also act as a signaling molecule. Although GlcNAc catabolism has been well studied in many pathogens, the importance of several enzymes involved in the formation of metabolic intermediates still remains elusive. In this context, microarray analysis was carried out to investigate the transcriptional responses induced by GlcNAc under different conditions. A novel gene that was highly upregulated immediately following the GlcNAc catabolic genes was identified and was named GIG2 (GlcNAc-induced gene 2). This gene is regulated in a manner distinct from that of the GlcNAc-induced genes described previously in that GlcNAc metabolism is essential for its induction. Furthermore, this gene is involved in the metabolism of N-acetylneuraminate (sialic acid), a molecule equally important for initial host-pathogen recognition. Mutant cells showed a considerable decrease in fungal burden in mouse kidneys and were hypersensitive to oxidative stress conditions. Since GIG2 is also present in many other fungal and enterobacterial genomes, targeted inhibition of its activity would offer insight into the treatment of candidiasis and other fungal or enterobacterial infections

CD4<SUP>+</SUP> T Cell-derived novel peptide Thp5 induces interleukin-4 production in CD4<SUP>+</SUP> T cells to direct T helper 2 cell differentiation

The differentiation of naïve CD4+ T cells into T helper 2 (Th2) cells requires production of the cytokine IL-4 in the local microenvironment. It is evident that naïve/quiescently activated CD4+ T cells produce the IL-4 that drives Th2 cell differentiation. Because early production of IL-4 in naïve T cells leads to preferential Th2 cell differentiation, this process needs to be tightly regulated so as to avoid catastrophic and misdirected Th2 cell differentiation. Here, we show that Thp5, a novel peptide with structural similarity to vasoactive intestinal peptide, regulates production of early IL-4 in newly activated CD4+ T cells. Induction of IL-4 in CD4+ T cells by Thp5 is independent of the transcription factor STAT6 but dependent on ERK1/2 signaling. Furthermore, cytokines (IL-12 and TGF-β) that promote the differentiation of Th1 or Th17 cells inhibit Thp5 induction, thus suppressing Th2 cell differentiation. We further showed that Thp5 enhances Th2 responses and exacerbates allergic airway inflammation in mice. Taken together, our findings reveal that early activated CD4+ T cells produce Thp5, which plays a critical role as a molecular switch in the differentiation of Th cells, biasing the response toward the Th2 cell phenotype

Understanding Oxidative Stress in Aedes during Chikungunya and Dengue Virus Infections Using Integromics Analysis

Arboviral infection causes dysregulation of cascade of events involving numerous biomolecules affecting fitness of mosquito to combat virus. In response of the viral infection mosquito&rsquo;s defense mechanism get initiated. Oxidative stress is among the first host responses triggered by the vector. Significant number of information is available showing changes in the transcripts and/or proteins upon Chikungunya virus and Dengue virus mono-infections and as co-infections. In the present study, we collected different -omics data available in the public database along with the data generated in our laboratory related to mono-infections or co-infections of these viruses. We analyzed the data and classified them into their respective pathways to study the role of oxidative stress in combating arboviral infection in Aedes mosquito. The analysis revealed that the oxidative stress related pathways functions in harmonized manner

Nuclear magnetic resonance based profiling of biofluids reveals metabolic dysregulation in HIV-infected persons and those on anti-retroviral therapy.

BACKGROUND: Although HIV causes immune deficiency by infection and depletion of immunocytes, metabolic alterations with clinical manifestations are also reported in HIV/AIDS patients. Here we aimed to profile metabolite changes in the plasma, urine, and saliva of HIV/AIDS patients, including those on anti-retroviral therapy (ART). METHODS: Metabolic profiling of biofluids collected from treatment naïve HIV/AIDS patients and those receiving ART was done with solution-state nuclear magnetic resonance (NMR) spectroscopy followed by statistical analysis and annotation. RESULTS: In Principal Component Analysis (PCA) of the NMR spectra, Principal Component 1 (PC1) alone accounted for 99.3%, 87.2% and 78.8% variations in plasma, urine, and saliva, respectively. Partial least squares discriminant analysis (PLS-DA) was applied to generate three-component models, which showed plasma and urine to be better than saliva in discriminating between patients and healthy controls, and between ART-naïve patients and those receiving therapy. Twenty-six metabolites were differentially altered in any or two types of samples. Our results suggest that urinary Neopterin, and plasma Choline and Sarcosine could be used as metabolic biomarkers of HIV/AIDS infection. Pathway analysis revealed significant alternations in 12 metabolic pathways. CONCLUSIONS: This study catalogs differentially regulated metabolites in biofluids, which helped classify subjects as healthy controls, HIV/AIDS patients, and those on ART. It also underscores the importance of further studying the consequences of HIV infection on host metabolism and its implications for pathogenesis

Targeting Drug-Sensitive and -Resistant Strains of Mycobacterium tuberculosis by Inhibition of Src Family Kinases Lowers Disease Burden and Pathology

ABSTRACT In view of emerging drug resistance among bacterial pathogens, including Mycobacterium tuberculosis, the development of novel therapeutic strategies is increasingly being sought. A recent paradigm in antituberculosis (anti-TB) drug development is to target the host molecules that are crucial for intracellular survival of the pathogen. We previously showed the importance of Src tyrosine kinases in mycobacterial pathogenesis. Here, we report that inhibition of Src significantly reduced survival of H37Rv as well as multidrug-resistant (MDR) and extremely drug-resistant (XDR) strains of M. tuberculosis in THP-1 macrophages. Src inhibition was also effective in controlling M. tuberculosis infection in guinea pigs. In guinea pigs, reduced M. tuberculosis burden due to Src inhibition also led to a marked decline in the disease pathology. In agreement with the theoretical framework of host-directed approaches against the pathogen, Src inhibition was equally effective against an XDR strain in controlling infection in guinea pigs. We propose that Src inhibitors could be developed into effective host-directed anti-TB drugs, which could be indiscriminately used against both drug-sensitive and drug-resistant strains of M. tuberculosis. IMPORTANCE The existing treatment regimen for tuberculosis (TB) suffers from deficiencies like high doses of antibiotics, long treatment duration, and inability to kill persistent populations in an efficient manner. Together, these contribute to the emergence of drug-resistant tuberculosis. Recently, several host factors were identified which help intracellular survival of Mycobacterium tuberculosis within the macrophage. These factors serve as attractive targets for developing alternate therapeutic strategies against M. tuberculosis. This strategy promises to be effective against drug-resistant strains. The approach also has potential to considerably lower the risk of emergence of new drug-resistant strains. We explored tyrosine kinase Src as a host factor exploited by virulent M. tuberculosis for intracellular survival. We show that Src inhibition can effectively control tuberculosis in infected guinea pigs. Moreover, Src inhibition ameliorated TB-associated pathology in guinea pigs. Thus, Src inhibitors have strong potential to be developed as possible anti-TB drugs

Parital least squares discrimination assay (PLS-DA) two-dimensional score plots developed from the ¹H NMR spectra of plasma, urine, and saliva collected from healthy control (X) and HIV/AIDS patients (Δ), and HIV/AIDS patients on ART (+).

<p>Parital least squares discrimination assay (PLS-DA) two-dimensional score plots developed from the ¹H NMR spectra of plasma, urine, and saliva collected from healthy control (X) and HIV/AIDS patients (Δ), and HIV/AIDS patients on ART (+).</p

Catalog of metabolites.

<p>The metabolites differentially regulated in plasma (p), urine (u) or saliva (s) in HIV/AIDS patients and patients on ART are shown. The arrows indicate lower (↓) or higher (↑) arbitrary levels of metabolites compared to healthy controls.</p

Metabolic pathways modulated in HIV/AIDS patients.

<p>The pathways that have at least 2 metabolites in the “hits” list and are differentially regulated in HIV/AIDS are shown.</p

Details of clinical samples.

<p>Details of clinical samples.</p