Nishanth Makthal

Nishanth Makthal
Houston Methodist Hospital | HOUSTONMETHODIST · Infectious diseases

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32
Publications
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373
Citations

Publications

Publications (32)
Article
Full-text available
Tissue injury is typically accompanied by inflammation. In Drosophila melanogaster, wound-induced inflammation involves adhesive capture of hemocytes at the wound surface followed by hemocyte spreading to assume a flat, lamellar morphology. The factors that mediate this cell spreading at the wound site are not known. Here, we discover a role for th...
Article
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Colonization by pathogenic bacteria depends on their ability to overcome host nutritional defenses and acquire nutrients. The human pathogen group A streptococcus (GAS) encounters host defense factor calprotectin (CP) during infection. CP inhibits GAS growth in vitro by imposing zinc (Zn) limitation. However, GAS counterstrategies to combat CP-medi...
Article
Full-text available
Bacteria control gene expression in concert with their population density by a process called quorum sensing, which is modulated by bacterial chemical signals and environmental factors. In the human pathogen Streptococcus pyogenes, production of secreted virulence factor SpeB is controlled by a quorum-sensing pathway and environmental pH. The quoru...
Article
Full-text available
Pathogenic bacteria encounter host-imposed manganese (Mn) limitation during infection. Herein we report that in the human pathogen Streptococcus pyogenes, the adaptive response to Mn limitation is controlled by a DtxR family metalloregulator, MtsR. Genes upregulated by MtsR during Mn limitation include Mn (mtsABC) and Fe acquisition systems (sia op...
Article
Full-text available
The control of virulence regulator/sensor kinase (CovRS) two-component system is critical to the infectivity of group A streptococcus (GAS), and CovRS inactivating mutations are frequently observed in GAS strains causing severe human infections. CovS modulates the phosphorylation status and with it the regulatory effect of its cognate regulator Cov...
Data
PrtS gene transcript level in various CovR/S isoallelic strains. Transcript levels (means ± standard deviations; n = 4) of prtS in the CovR/S-deleted or mutated strains relative to those of the wild type, as measured by TaqMan qRT-PCR. Strains were grown in THY to mid-exponential phase. * = P < 0.05 for gene transcript level in indicated strain rel...
Data
Influence of CovR~P on transcript levels of genes representing distinct classes. (A) Schematic depiction of CovR~P levels in the indicated GAS strains. Values were derived from previous Phostag-Western blot analyses of CovR~P status. (B-D) Transcript levels (means ± standard deviations; n = 4) of indicated genes that are representative for distinct...
Data
Selected genes differentially regulated in the indicated strains compared to respective wild type strain. (DOCX)
Data
Milk plate assay. SpeB protease activity was assessed by the size of a clear zone around the bacterial growth on casein milk agar plates. Strains shown clockwise are WT = MGAS10870 (M3-WT), R66H = M3-CovR-R66H, L155I = M3-CovR-L155I, A81T = M3-CovR-A81T, P285S = M3-CovS-P285S, and ΔS = M3ΔcovS. (TIF)
Data
Plasmids, primers and probes. (DOCX)
Data
DNase activity of wild-type and CovS-T284A derivatives. DNase activity of culture supernatants was determined as described in the Materials and Methods. Shown is mean ± standard deviation of residual DNA following incubation with filtered supernatant of indicated strains. Experiments were performed in triplicate on two separate days. * = P < 0.05 f...
Article
Full-text available
Bacterial virulence factor production is a highly coordinated process. The temporal pattern of bacterial gene expression varies in different host anatomic sites to overcome niche-specific challenges. The human pathogen group A streptococcus (GAS) produces a potent secreted protease, SpeB, that is crucial for pathogenesis. Recently, we discovered th...
Article
Group A Streptococccus (GAS) is a major human pathogen that causes significant morbidity and mortality. Zinc is an essential trace element required for GAS growth, however, zinc can be toxic at excess concentration. The bacterial strategies to maintain zinc sufficiency without incurring zinc toxicity plays a crucial role in host-GAS interactions an...
Article
Full-text available
Successful pathogens use complex signaling mechanisms to monitor their environment and reprogram global gene expression during specific stages of infection. Group A Streptococcus (GAS) is a major human pathogen that causes significant disease burden worldwide. A secreted cysteine protease known as streptococcal pyrogenic exotoxin B (SpeB) is a key...
Article
Full-text available
There is an urgent need for a human vaccine to protect against diseases caused by human pathogen, group A streptococcus (GAS). Herein, we identified the key molecular players involved in the battle between the host and invading bacteria for the critical nutrient zinc. The host recruits calprotectin at GAS infection sites to limit zinc availability...
Article
Group A streptococcus (GAS) is a human-only pathogen that causes a spectrum of disease conditions. Given its survival in inflamed lesions, the ability to sense and overcome oxidative stress is critical for GAS pathogenesis. PerR senses oxidative stress and coordinates the regulation of genes involved in GAS antioxidant defenses. In this study, we i...
Article
Importance: The modulation of gene transcription is key to the ability of bacterial pathogens to infect and cause disease. Here, we not only discovered that the group A Streptococcus transcription factor RivR negatively regulates the ability of this pathogen to survive in human blood, but also began a biochemical characterization of this protein....
Article
Full-text available
Group A Streptococcus (GAS) is an exclusive human pathogen that causes significant disease burden. Global regulator RopB of GAS controls the expression of several major virulence factors including secreted protease SpeB during high cell density. However, the molecular mechanism for RopB-dependent speB expression remains unclear. To understand the m...
Article
Full-text available
Importance: More than half a million deaths each year are a consequence of infections caused by the group A Streptococcus (GAS). Insights into how this pathogen regulates the production of proteins during infection may facilitate the development of novel therapeutic or preventative regimes aimed at inhibiting this activity. Here, we have expanded...
Article
Full-text available
Whole genome sequencing analysis of ∼ 800 strains of group A Streptococcus (GAS) found that the gene encoding multiple virulence gene regulator of GAS (mga) is highly polymorphic in serotype M59 strains but not other serotypes. To help understand the molecular mechanism of gene regulation by Mga and its contribution to GAS pathogenesis in serotype...
Article
Full-text available
Altering zinc bioavailability to bacterial pathogens is a key component of host innate immunity. Thus, the ability to sense and adapt to the alterations in zinc concentrations is critical for bacterial survival and pathogenesis. To understand the adaptive responses of group A Streptococcus (GAS) to zinc limitation and its regulation by AdcR, we cha...
Article
Full-text available
Single-nucleotide polymorphisms (SNPs) are the most common source of genetic variation within a species; however, few investigations demonstrate how naturally occurring SNPs may increase strain virulence. We recently used group A Streptococcus as a model pathogen to study bacteria strain genotype-patient disease phenotype relationships. Whole-genom...
Article
Full-text available
Regulation of oxidative stress responses by the peroxide stress regulator (PerR) is critical for the in vivo fitness and virulence of group A Streptococcus. To elucidate the molecular mechanism of DNA binding, peroxide sensing, and gene regulation by PerR, we performed biochemical and structural characterization of PerR. Sequence-specific DNA bindi...
Article
Streptococcal pyrogenic exotoxin B (SpeB) is an extracellular cysteine protease that is a critical virulence factor made by the major human pathogen group A Streptococcus (GAS). speB expression is dependent on the regulator of proteinase B (RopB) and is upregulated with increasing cell density and during infection. Because computer modelling sugges...

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