Himanshu Kumar - Profile on Academia.edu (original) (raw)

Papers by Himanshu Kumar

Chemical Science

A redox-active anticancer Au(i) complex that induces immunogenic cell death in non-small cell lun... more A redox-active anticancer Au(i) complex that induces immunogenic cell death in non-small cell lung cancer cells has been identified. Mitochondrial oxidative stress leading to mitophagy-dependent secretion of various DAMPs is implicated as the main mechanism inducing ICD.

Cell Death & Disease

Intracellular and cell surface pattern-recognition receptors (PRRs) are an essential part of inna... more Intracellular and cell surface pattern-recognition receptors (PRRs) are an essential part of innate immune recognition and host defense. Here, we have compared the innate immune responses between humans and bats to identify a novel membrane-associated protein, Rnd1, which defends against viral and bacterial infection in an interferon-independent manner. Rnd1 belongs to the Rho GTPase family, but unlike other small GTPase members, it is constitutively active. We show that Rnd1 is induced by pro-inflammatory cytokines during viral and bacterial infections and provides protection against these pathogens through two distinct mechanisms. Rnd1 counteracts intracellular calcium fluctuations by inhibiting RhoA activation, thereby inhibiting virus internalisation. On the other hand, Rnd1 also facilitates pro-inflammatory cytokines IL-6 and TNF-α through Plxnb1, which are highly effective against intracellular bacterial infections. These data provide a novel Rnd1-mediated innate defense again...

Immunogenic Cell Death (ICD) is a unique cell death mechanism that kills cancer cells while rejuv... more Immunogenic Cell Death (ICD) is a unique cell death mechanism that kills cancer cells while rejuvenating the anti-cancer immunosurveillance, thereby benefiting the clinical outcomes of various chemo-immunotherapeutic regimens. Herein, we report development of a library of Benzo[a]quinolizinium-based Au(I) complexes through an intramolecular amino-auration reaction of pyridino-alkynes. We tested 40 candidates and successfully identified BQ-AurIPr as a novel redox-active Au(I) complex with potent anticancer properties. BQ-AurIPr efficiently triggered generation of DAMPs-the hallmarks of ICD, and was superior in terms of efficiency compared to FDA-approved drugs known to in-duce ICD. BQ-AurIPr significantly increased immunogenicity of cancer cells enhancing their phagocytosis when co-cultured with immune cells. Our investigation reveals that BQ-AurIPr induces oxidative stress inside mitochondria leading to mitophagy, as the mechanism for ICD induction.

iScience, 2021

Programmed cell death pathways are triggered by various stresses or stimuli, including viral infe... more Programmed cell death pathways are triggered by various stresses or stimuli, including viral infections. The mechanism underlying the regulation of these pathways upon Influenza A virus IAV infection is not well characterized. We report that a cytosolic DNA sensor IFI16 is essential for the activation of programmed cell death pathways in IAV infected cells. We have identified that IFI16 functions as an RNA sensor for influenza A virus by binding to genomic RNA. The activation of IFI16 triggers the production of type I, III interferons, and also other pro-inflammatory cytokines via the STING-TBK1 and Pro-caspase-1 signaling axis, thereby promoting cell death (apoptosis and pyroptosis in IAV infected cells). Whereas, IFI16 knockdown cells showed reduced inflammatory responses and also prevented cell mortality during IAV infection. These results demonstrate the pivotal role of IFI16-mediated IAV sensing and its essential role in activating programmed cell death pathways.

Environmental Pollution, 2020

Since January 2020 Elsevier has created a COVID-19 resource centre with free information in Engli... more Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre -including this research content -immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

Frontiers in Cellular and Infection Microbiology, 2021

Host innate immunity is the major player against continuous microbial infection. Various pathogen... more Host innate immunity is the major player against continuous microbial infection. Various pathogenic bacteria adopt the strategies to evade the immunity and show resistance toward the various established therapies. Despite the advent of many antibiotics for bacterial infections, there is a substantial need for the host-directed therapies (HDTs) to combat the infection. HDTs are recently being adopted to be useful in eradicating intracellular bacterial infection. Changing the innate immune responses of the host cells alters pathogen’s ability to reside inside the cell. MicroRNAs are the small non-coding endogenous molecules and post-transcriptional regulators to target the 3’UTR of the messenger RNA. They are reported to modulate the host’s immune responses during bacterial infections. Exploiting microRNAs as a therapeutic candidate in HDTs upon bacterial infection is still in its infancy. Here, initially, we re-analyzed the publicly available transcriptomic dataset of macrophages, in...

ABSTRACTSensing of pathogens by specialized receptors is the hallmark of the innate immune respon... more ABSTRACTSensing of pathogens by specialized receptors is the hallmark of the innate immune response. Innate immune response also mounts a defense response against various allergens and pollutants including particulate matter present in the atmosphere. Air pollution has been included as the top threat to global health declared by WHO which aims to cover more than three billion people against health emergencies from 2019-2023. Particulate matter (PM), one of the major components of air pollution, is a significant risk factor for many human diseases and its adverse effects include morbidity and premature deaths throughout the world. Several clinical and epidemiological studies have identified a key link between the PM composition and the prevalence of respiratory and inflammatory disorders. However, the underlying molecular mechanism is not well understood. Here, we investigated the influence of air pollutant, PM10 during RNA virus infections using highly pathogenic avian influenza (HP...

SSRN Electronic Journal, 2020

Precise regulation of innate immunity is crucial for the development of appropriate host immunity... more Precise regulation of innate immunity is crucial for the development of appropriate host immunity against microbial infections and the maintenance of immune homeostasis. The microRNAs are small non-coding RNA, post-transcriptional regulator of multiple genes and act as a rheostat for protein expression. Here, we identified microRNA(miR)-30e-5p (miR-30e) induced by the hepatitis B virus (HBV) and other viruses that act as a master regulator for innate immune responses. Moreover, pegylated type I interferons treatment to HBV patients for viral reduction also reduces the miRNA. Additionally, we have also shown the immuno-pathological effects of miR-30e in systemic lupus erythematous (SLE) patients and SLE mouse model. Mechanistically, the miR-30e targets multiple negative regulators namely TRIM38, TANK, ATG5, ATG12, BECN1, SOCS1, SOCS3 of innate immune signaling pathways and enhances innate immune responses. Furthermore, sequestering of endogenous miR-30e in PBMCs of SLE patients and SLE mouse model respectively by the introduction of antagomir and locked nucleic acid based inhibitor significantly reduces type I interferon and pro-inflammatory cytokines. Collectively, our study demonstrates the novel role of miR-30e in innate immunity and its prognostic and therapeutic potential in infectious and autoimmune diseases.

Frontiers in Immunology, 2020

MicroRNAs are short non-coding RNAs that play a crucial role in the regulation of gene expression... more MicroRNAs are short non-coding RNAs that play a crucial role in the regulation of gene expression during cellular processes. The host-encoded miRNAs are known to modulate the antiviral defense during viral infection. In the last decade, multiple DNA and RNA viruses have been shown to produce miRNAs known as viral miRNAs (v-miRNAs) so as to evade the host immune response. In this review, we highlight the origin and biogenesis of viral miRNAs during the viral lifecycle. We also explore the role of viral miRNAs in immune evasion and hence in maintaining chronic infection and disease. Finally, we offer insights into the underexplored role of viral miRNAs as potential targets for developing therapeutics for treating complex viral diseases.

Nutrients, Jan 21, 2018

The composition of human breast milk is highly variable, and it can be influenced by genetics, di... more The composition of human breast milk is highly variable, and it can be influenced by genetics, diet, lifestyle, and other environmental factors. This study aimed to investigate the impact of geographical location and mode of delivery on the nuclear magnetic resonance spectroscopy (NMR) metabolic profile of breast milk and its relationship with the milk microbiome. Human milk metabolic and microbiota profiles were determined using NMR and 16S rRNA gene sequencing, respectively, in 79 healthy women from Finland, Spain, South Africa, and China. Up to 68 metabolites, including amino acids, oligosaccharides, and fatty acid-associated metabolites, were identified in the milk NMR spectra. The metabolite profiles showed significant differences between geographical locations, with significant differences ( < 0.05) in the levels of galactose, lacto--fucopentaose III, lacto--fucopentaose I and 2-fucosyllactose, 3-fucosyllactose, lacto--difucohexaose II, lacto--fucopentaose III, 2-hydroxybut...

Journal of virology, Oct 25, 2018

MicroRNAs (miRNAs) are small non-coding RNAs that are crucial post-transcriptional regulator for ... more MicroRNAs (miRNAs) are small non-coding RNAs that are crucial post-transcriptional regulator for host mRNAs. Recent studies indicate that miRNAs may modulate host response during RNA viruses infection. However, the role of miRNAs in immune response against H5N1 infection is not clearly understood. In this study, we show that expression of cellular miRNA, miR-324-5p was downregulated in A549 cells in response to infection with RNA viruses, H5N1, A/PR8/H1N1, and NDV and transfection with polyI:C. We found that miR-324-5p inhibited H5N1 replication by targeting the PB1 viral RNA of H5N1 in host cells. In addition, transcriptome analysis revealed that miR-324-5p enhanced the expression of Type-I, Type-III interferons, and interferons-inducible genes (ISGs) by targeting CUEDC2, the negative regulator of JAK1-STAT3 pathway. Altogether, these findings highlights that the miR-324-5p plays a crucial role in host defense against H5N1 by targeting viral PB1 and host CUEDC2 to inhibit H5N1 repl...

FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Jan 23, 2018

White adipose tissue inflammation is linked with increased aromatase gene expression and estrogen... more White adipose tissue inflammation is linked with increased aromatase gene expression and estrogen production, a major risk factor for breast cancer in obese postmenopausal women. TNF-α, a proinflammatory cytokine, is a key driver of aromatase promoter I.4-mediated expression in adipose tissue. In this study, we have shown that IL-10, an anti-inflammatory cytokine, suppressed both TNF-α-stimulated human aromatase reporter-luciferase (hARO-Luc) expression in mouse bone marrow mesenchymal stromal cells and aromatase gene expression in human breast adipose stromal cells (ASCs). IL-10 blocked TNF-α-stimulated ERK1/2 activation in ASCs, suggesting an inhibitory effect through the MAPK signaling pathway. The links among obesity, IL-10, and aromatase were confirmed in ovariectomized (OVX) hARO-Luc mice, where increased adiposity was associated with upregulation of aromatase reporter activity and reduced IL-10 level in the mammary fat pad. OVX mice also exhibited changes in gut microbiota, s...

International reviews of immunology, Sep 3, 2017

Cell death & disease, Oct 5, 2017

Cancer is a multifactorial disease and virus-mediated carcinogenesis is one of the crucial factor... more Cancer is a multifactorial disease and virus-mediated carcinogenesis is one of the crucial factors, which is poorly understood. Human cytomegalovirus (HCMV) is a herpesvirus and its components have been evidenced to be associated with cancer of different tissue origin. However, its role in cancer remains unknown. Here, we identified a conserved herpesviral tegument protein known as pUL48 of HCMV, encoding deubiquitinase enzyme, as having a key role in carcinogenesis. We show using deubiquitinase sufficient- and deficient-HCMV that HCMV deubiquitinase is a key in inducing enhanced cellular metabolic activity through upregulation of several anti-apoptotic genes and downregulation of several pro-apoptotic genes expression. Furthermore, HCMV deubiquitinase acquires pro-tumor functions by inhibiting PRR-mediated type I interferon via deubiquitination of TRAF6, TRAF3, IRAK1, IRF7 and STING. Taken together, our results suggest that HCMV infection may promote oncogenesis by inhibiting innat...

ABSTRACTDroplet based single cell transcriptomics has recently enabled parallel screening of tens... more ABSTRACTDroplet based single cell transcriptomics has recently enabled parallel screening of tens of thousands of single cells. Clustering methods that scale for such high dimensional data without compromising accuracy are scarce. We exploit Locality Sensitive Hashing, an approximate nearest neighbor search technique to develop ade novoclustering algorithm for large-scale single cell data. On a number of real datasets, dropClust outperformed the existing best practice methods in terms of execution time, clustering accuracy and detectability of minor cell sub-types.

International reviews of immunology, May 10, 2017

International reviews of immunology, Mar 4, 2017

Science signaling, Jan 8, 2015

MicroRNAs (miRNAs) are small noncoding RNAs that are responsible for dynamic changes in gene expr... more MicroRNAs (miRNAs) are small noncoding RNAs that are responsible for dynamic changes in gene expression, and some regulate innate antiviral responses. Retinoic acid-inducible gene I (RIG-I) is a cytosolic sensor of viral RNA; RIG-I activation induces an antiviral immune response. We found that miR-485 of the host was produced in response to viral infection and targeted RIG-I mRNA for degradation, which led to suppression of the antiviral response and enhanced viral replication. Thus, inhibition of the expression of mir-485 markedly reduced the replication of Newcastle disease virus (NDV) and the H5N1 strain of influenza virus in mammalian cells. Unexpectedly, miR-485 also bound to the H5N1 gene PB1 (which encodes an RNA polymerase required for viral replication) in a sequence-specific manner, thereby inhibiting replication of the H5N1 virus. Furthermore, miR-485 exhibited bispecificity, targeting RIG-I in cells with a low abundance of H5N1 virus and targeting PB1 in cells with incre...

Cell death & disease, 2015

RIG-I-like receptors are the key cytosolic sensors for RNA viruses and induce the production of t... more RIG-I-like receptors are the key cytosolic sensors for RNA viruses and induce the production of type I interferons (IFN) and pro-inflammatory cytokines through a sole adaptor IFN-β promoter stimulator-1 (IPS-1) (also known as Cardif, MAVS and VISA) in antiviral innate immunity. These sensors also have a pivotal role in anticancer activity through induction of apoptosis. However, the mechanism for their anticancer activity is poorly understood. Here, we show that anticancer vaccine adjuvant, PolyIC (primarily sensed by MDA5) and the oncolytic virus, Newcastle disease virus (NDV) (sensed by RIG-I), induce anticancer activity. The ectopic expression of IPS-1 into type I IFN-responsive and non-responsive cancer cells induces anticancer activity. PolyIC transfection and NDV infection upregulate pro-apoptotic gene TRAIL and downregulate the anti-apoptotic genes BCL2, BIRC3 and PRKCE. Furthermore, stable knockdown of IPS-1, IRF3 or IRF7 in IFN-non-responsive cancer cells show reduced antic...

Frontiers in Immunology, 2013

Innate sensors play a critical role in the early innate immune responses to invading pathogens th... more Innate sensors play a critical role in the early innate immune responses to invading pathogens through sensing of diverse biochemical signatures also known as pathogen associated molecular patterns (PAMPs). These biochemical signatures primarily consist of a major family of biomolecules such as proteins, lipids, nitrogen bases, and sugar and its complexes, which are distinct from host molecules and exclusively expressed in pathogens and essential to their survival.The family of sensors known as pattern recognition receptors (PRRs) are germ-line encoded, evolutionarily conserved molecules, and consist of Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), NOD-like receptors (NLRs), C-type lectinlike receptors (CLRs), and DNA sensors. Sensing of PAMP by PRR initiates the cascade of signaling leading to the activation of transcription factors, such as NF-κB and interferon regulatory factors (IRFs), resulting in a variety of cellular responses, including the production of interferons (IFNs) and pro-inflammatory cytokines. In this review, we discuss sensing of different types of glycosylated PAMPs such as β-glucan (a polymeric sugar) or lipopolysaccharides, nucleic acid, and so on (sugar complex PAMPs) by different families of sensors, its role in pathogenesis, and its application in development of potential vaccine and vaccine adjuvants.