Tarun Keswani | University of Calcutta (original) (raw)

Papers by Tarun Keswani

Research paper thumbnail of Plasmodium yoelii Uses a TLR3-Dependent Pathway to Achieve Mammalian Host Parasitism

The Journal of Immunology, 2020

Key Points P. yoelii 265 BY liver stage triggers TLR3-dependent signaling pathways. TLR3 KO mice ... more Key Points P. yoelii 265 BY liver stage triggers TLR3-dependent signaling pathways. TLR3 KO mice better controlled liver and blood stage parasites growth. TLR3 participates in early IFN-γ and delayed type I IFNs production. Malaria is associated with complicated immunopathogenesis. In this study, we provide evidence for an unexpected role of TLR3 in promoting the establishment of Plasmodium yoelii infection through delayed clearance of parasitemia in wild type C57BL/6jRj (B6) compared with TLR3 knockout mice. In this study, we confirmed an increased expression of Tlr3, Trif, Tbk1, and Irf7/Irf3 in the liver 42 h postinfection and the initiation of an early burst of proinflammatory response such as Ifng, NF-kB, and Tnfa in B6 mice that may promote parasite fitness. Interestingly, in the absence of TLR3, we showed the involvement of high IFN-γ and lower type I IFN response in the early clearance of parasitemia. In parallel, we observed an increase in splenic NK and NKT cells expressing TLR3 in infected B6 mice, suggesting a role for TLR sensing in the innate immune response. Finally, we find evidence that the increase in the frequency of CD19+TLR3+ B cells along with reduced levels of total IgG in B6 mice possibly suggests the initiation of TLR3-dependent pathway early during P. yoelii infection. Our results thus reveal a new mechanism in which a parasite-activated TLR3 pathway promotes blood stage infection along with quantitative and qualitative differences in Ab responses.

Research paper thumbnail of Expression of CD300lf by microglia contributes to resistance to cerebral malaria by impeding the neuroinflammation

Genes & Immunity, 2019

Genetic mapping and genome-wide studies provide evidence for the association of several genetic p... more Genetic mapping and genome-wide studies provide evidence for the association of several genetic polymorphisms with malaria, a complex pathological disease with multiple severity degrees. We have previously described Berr1and Berr2 as candidate genes identified in the WLA/Pas inbreed mouse strain predisposing to resistance to cerebral malaria (CM) induced by P. berghei ANKA. We report in this study the phenotypic and functional characteristics of a congenic strain we have derived for Berr2 WLA allele on the C57BL/6JR (B6) background. B6.WLA-Berr2 was found highly resistant to CM compared to C57BL/6JR susceptible mice. The mechanisms associated with CM resistance were analyzed by combining genotype, transcriptomic and immune response studies. We found that B6.WLA-Berr2 mice showed a reduced parasite sequestration and blood-brain barrier disruption with low CXCR3 + T cell infiltration in the brain along with altered glial cell response upon P. berghei ANKA infection compared to B6. In addition, we have identified the CD300f, belonging to a family of Ig-like encoding genes, as a potential candidate associated with CM resistance. Microglia cells isolated from the brain of infected B6.WLA-Berr2 mice significantly expressed higher level of CD300f compared to CM S mice and were associated with inhibition of inflammatory response.

Research paper thumbnail of Immunotherapy-induced neutralizing antibodies disrupt allergen binding and sustain allergen tolerance in peanut allergy

Journal of Clinical Investigation

Research paper thumbnail of Suppression of CD4 + Effector Responses by Naturally Occurring CD4 + CD25 + Foxp3 + Regulatory T Cells Contributes to Experimental Cerebral Malaria

Infection and Immunity, 2015

The role of naturally occurring CD4(+) CD25(+) Foxp3(+) regulatory T cells (nTreg) in the pathoge... more The role of naturally occurring CD4(+) CD25(+) Foxp3(+) regulatory T cells (nTreg) in the pathogenesis of cerebral malaria (CM), which involves both pathogenic T cell responses and parasite sequestration in the brain, is still unclear. To assess the contribution and dynamics of nTreg during the neuropathogenesis, we unbalanced the ratio between nTreg and naive CD4(+) T cells in an attenuated model of Plasmodium berghei ANKA-induced experimental CM (ECM) by using a selective cell enrichment strategy. We found that nTreg adoptive transfer accelerated the onset and increased the severity of CM in syngeneic C57BL/6 (B6) P. berghei ANKA-infected mice without affecting the level of parasitemia. In contrast, naive CD4(+) T cell enrichment prevented CM and promoted parasite clearance. Furthermore, early during the infection nTreg expanded in the spleen but did not efficiently migrate to the site of neuroinflammation, suggesting that nTreg exert their pathogenic action early in the spleen by suppressing the protective naive CD4(+) T cell response to P. berghei ANKA infection in vivo in both CM-susceptible (B6) and CM-resistant (B6-CD4(-/-)) mice. However, their sole transfer was not sufficient to restore CM susceptibility in two CM-resistant congenic strains tested. Altogether, these results demonstrate that nTreg are activated and functional during P. berghei ANKA infection and that they contribute to the pathogenesis of CM. They further suggest that nTreg may represent an early target for the modulation of the immune response to malaria.

Research paper thumbnail of Palladium(II) Complex Induces Apoptosis through ROS-Mediated Mitochondrial Pathway in human lung adenocarcinoma cell line (A549)

Research paper thumbnail of Dendritic Cells subsets mediated immune response during Plasmodium berghei ANKA and Plasmodium yoelii infection.

Research paper thumbnail of Keswani T and Bhattacharyya A. Differential role of T Regulatory and Th17 in Swiss mice infected with Plasmodium berghei ANKA and Plasmodium yoelii. Experimental Parasitology, 2014; 141:82-92.

Research paper thumbnail of Karthik L, Kumar G, Keswani T, et al., Protease inhibitors from Marine actinobacteria as a potential source for antimalarial compound. Plos One, 2014; 11;9(3):e90972

Research paper thumbnail of Keswani T, Mitra S, Bhattacharyya A. Copper-Induced Immunotoxicity Involves Cell Cycle Arrest and Cell Death in the liver. Environmental Toxicology, 2013

Research paper thumbnail of Copper induced immunotoxicity promote differential apoptotic pathways in spleen and thymus.

Research paper thumbnail of Marine actinobacterial mediated gold nanoparticles synthesis and their antimalarial activity

Research paper thumbnail of Effects of Pentoxifylline on Liver and Thymus of Plasmodium berghei ANKA Infected Swiss Albino Mice

Research paper thumbnail of Copper-induced immunotoxicity involves cell cycle arrest and cell death in the spleen and thymus.

Copper is an essential trace element for human physiological processes. To evaluate the potential... more Copper is an essential trace element for human physiological processes. To evaluate the potential adverse health impact/immunotoxicological effects of this metal in situ due to over exposure, Swiss albino mice were treated (via intraperitoneal injections) with copper (II) chloride (copper chloride) at doses of 0, 5, or 7.5 mg copper chloride/kg body weight (b.w.) twice a week for 4 wk; these values were derived from LD₅₀ studies using copper chloride doses that ranged from 0 to 40 mg/kg BW (2×/wk, for 4 wk). Copper treated mice evidenced immunotoxicity as indicated by dose-related decreases and increases, respectively, in thymic and splenic weights. Histomorphological changes evidenced in these organs were thymic atrophy, white pulp shrinkage in the spleen, and apoptosis of splenocytes and thymocytes; these observations were confirmed by microscopic analyses. Cell count analyses indicated that the proliferative functions of the splenocytes and thymocytes were also altered because of the copper exposures. Among both cell types from the copper treated hosts, flow cytometric analyses revealed a dose related increase in the percentages of cells in the Sub-G₀/G₁ state, indicative of apoptosis which was further confirmed by Annexin V binding assay. In addition, the copper treatments altered the expression of selected cell death related genes such as EndoG and Bax in a dose related manner. Immunohistochemical analyses revealed that there was also increased ubiquitin expression in both the cell types. In conclusion, these studies show that sublethal exposure to copper (as copper chloride) induces toxicity in the thymus and spleen, and increased Sub G₀/G₁ population among splenocytes and thymocytes that is mediated, in part, by the EndoG-Bax-ubiquitin pathway. This latter damage to these cells that reside in critical immune system organs are likely to be important contributing factors underlying the immunosuppression that has been documented by other investigators following acute high dose/chronic low-medium dose exposures to copper agents.Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Research paper thumbnail of Splenocyte apoptosis in Plasmodium berghei ANKA infection: Possible Role of TNF- α and TGF- β

Cerebral malaria is associated with the circulating levels of tumour necrosis factor alpha (TNF-α... more Cerebral malaria is associated with the circulating levels of tumour necrosis factor alpha (TNF-α) and transforming growth factor β (TGF-β), but association between these two cytokines and implications in splenocyte apoptosis remain largely obscured. We have evaluated the outcome of TGF-β and TNF-α production in the context of splenocyte apoptosis during Plasmodium berghei ANKA (PbA) infection. Blood-stage PbA infection confirmed blood-brain barrier disruption, disarray of white pulp, increase in percentage of sub-G0/G1 and splenocyte apoptosis. Flow cytometric analysis reveals up-regulation of Fas-L followed by caspase-8 and caspase-3 activation and signifies possible involvement of Fas-L-mediated splenocyte apoptosis. We have observed down-regulation of TGF-β and up-regulation of TNF-α in tissue and serum level, respectively, during PbA infection. Association between the production of TGF-β and the severity of malaria infection in splenocytes was verified with TGF-β inhibitor that exacerbated the apoptotic process. In contrary, TNF-α inhibitor causes significant delay in apoptotic process, but could not alter the lethality of parasite. Thus, results from this study suggest that the critical balance between TGF-β and TNF-α might have a key role on Fas-L-mediated splenocyte apoptosis during experimental cerebral malaria.© 2012 Blackwell Publishing Ltd.

Research paper thumbnail of Plasmodium yoelii Uses a TLR3-Dependent Pathway to Achieve Mammalian Host Parasitism

The Journal of Immunology, 2020

Key Points P. yoelii 265 BY liver stage triggers TLR3-dependent signaling pathways. TLR3 KO mice ... more Key Points P. yoelii 265 BY liver stage triggers TLR3-dependent signaling pathways. TLR3 KO mice better controlled liver and blood stage parasites growth. TLR3 participates in early IFN-γ and delayed type I IFNs production. Malaria is associated with complicated immunopathogenesis. In this study, we provide evidence for an unexpected role of TLR3 in promoting the establishment of Plasmodium yoelii infection through delayed clearance of parasitemia in wild type C57BL/6jRj (B6) compared with TLR3 knockout mice. In this study, we confirmed an increased expression of Tlr3, Trif, Tbk1, and Irf7/Irf3 in the liver 42 h postinfection and the initiation of an early burst of proinflammatory response such as Ifng, NF-kB, and Tnfa in B6 mice that may promote parasite fitness. Interestingly, in the absence of TLR3, we showed the involvement of high IFN-γ and lower type I IFN response in the early clearance of parasitemia. In parallel, we observed an increase in splenic NK and NKT cells expressing TLR3 in infected B6 mice, suggesting a role for TLR sensing in the innate immune response. Finally, we find evidence that the increase in the frequency of CD19+TLR3+ B cells along with reduced levels of total IgG in B6 mice possibly suggests the initiation of TLR3-dependent pathway early during P. yoelii infection. Our results thus reveal a new mechanism in which a parasite-activated TLR3 pathway promotes blood stage infection along with quantitative and qualitative differences in Ab responses.

Research paper thumbnail of Expression of CD300lf by microglia contributes to resistance to cerebral malaria by impeding the neuroinflammation

Genes & Immunity, 2019

Genetic mapping and genome-wide studies provide evidence for the association of several genetic p... more Genetic mapping and genome-wide studies provide evidence for the association of several genetic polymorphisms with malaria, a complex pathological disease with multiple severity degrees. We have previously described Berr1and Berr2 as candidate genes identified in the WLA/Pas inbreed mouse strain predisposing to resistance to cerebral malaria (CM) induced by P. berghei ANKA. We report in this study the phenotypic and functional characteristics of a congenic strain we have derived for Berr2 WLA allele on the C57BL/6JR (B6) background. B6.WLA-Berr2 was found highly resistant to CM compared to C57BL/6JR susceptible mice. The mechanisms associated with CM resistance were analyzed by combining genotype, transcriptomic and immune response studies. We found that B6.WLA-Berr2 mice showed a reduced parasite sequestration and blood-brain barrier disruption with low CXCR3 + T cell infiltration in the brain along with altered glial cell response upon P. berghei ANKA infection compared to B6. In addition, we have identified the CD300f, belonging to a family of Ig-like encoding genes, as a potential candidate associated with CM resistance. Microglia cells isolated from the brain of infected B6.WLA-Berr2 mice significantly expressed higher level of CD300f compared to CM S mice and were associated with inhibition of inflammatory response.

Research paper thumbnail of Immunotherapy-induced neutralizing antibodies disrupt allergen binding and sustain allergen tolerance in peanut allergy

Journal of Clinical Investigation

Research paper thumbnail of Suppression of CD4 + Effector Responses by Naturally Occurring CD4 + CD25 + Foxp3 + Regulatory T Cells Contributes to Experimental Cerebral Malaria

Infection and Immunity, 2015

The role of naturally occurring CD4(+) CD25(+) Foxp3(+) regulatory T cells (nTreg) in the pathoge... more The role of naturally occurring CD4(+) CD25(+) Foxp3(+) regulatory T cells (nTreg) in the pathogenesis of cerebral malaria (CM), which involves both pathogenic T cell responses and parasite sequestration in the brain, is still unclear. To assess the contribution and dynamics of nTreg during the neuropathogenesis, we unbalanced the ratio between nTreg and naive CD4(+) T cells in an attenuated model of Plasmodium berghei ANKA-induced experimental CM (ECM) by using a selective cell enrichment strategy. We found that nTreg adoptive transfer accelerated the onset and increased the severity of CM in syngeneic C57BL/6 (B6) P. berghei ANKA-infected mice without affecting the level of parasitemia. In contrast, naive CD4(+) T cell enrichment prevented CM and promoted parasite clearance. Furthermore, early during the infection nTreg expanded in the spleen but did not efficiently migrate to the site of neuroinflammation, suggesting that nTreg exert their pathogenic action early in the spleen by suppressing the protective naive CD4(+) T cell response to P. berghei ANKA infection in vivo in both CM-susceptible (B6) and CM-resistant (B6-CD4(-/-)) mice. However, their sole transfer was not sufficient to restore CM susceptibility in two CM-resistant congenic strains tested. Altogether, these results demonstrate that nTreg are activated and functional during P. berghei ANKA infection and that they contribute to the pathogenesis of CM. They further suggest that nTreg may represent an early target for the modulation of the immune response to malaria.

Research paper thumbnail of Palladium(II) Complex Induces Apoptosis through ROS-Mediated Mitochondrial Pathway in human lung adenocarcinoma cell line (A549)

Research paper thumbnail of Dendritic Cells subsets mediated immune response during Plasmodium berghei ANKA and Plasmodium yoelii infection.

Research paper thumbnail of Keswani T and Bhattacharyya A. Differential role of T Regulatory and Th17 in Swiss mice infected with Plasmodium berghei ANKA and Plasmodium yoelii. Experimental Parasitology, 2014; 141:82-92.

Research paper thumbnail of Karthik L, Kumar G, Keswani T, et al., Protease inhibitors from Marine actinobacteria as a potential source for antimalarial compound. Plos One, 2014; 11;9(3):e90972

Research paper thumbnail of Keswani T, Mitra S, Bhattacharyya A. Copper-Induced Immunotoxicity Involves Cell Cycle Arrest and Cell Death in the liver. Environmental Toxicology, 2013

Research paper thumbnail of Copper induced immunotoxicity promote differential apoptotic pathways in spleen and thymus.

Research paper thumbnail of Marine actinobacterial mediated gold nanoparticles synthesis and their antimalarial activity

Research paper thumbnail of Effects of Pentoxifylline on Liver and Thymus of Plasmodium berghei ANKA Infected Swiss Albino Mice

Research paper thumbnail of Copper-induced immunotoxicity involves cell cycle arrest and cell death in the spleen and thymus.

Copper is an essential trace element for human physiological processes. To evaluate the potential... more Copper is an essential trace element for human physiological processes. To evaluate the potential adverse health impact/immunotoxicological effects of this metal in situ due to over exposure, Swiss albino mice were treated (via intraperitoneal injections) with copper (II) chloride (copper chloride) at doses of 0, 5, or 7.5 mg copper chloride/kg body weight (b.w.) twice a week for 4 wk; these values were derived from LD₅₀ studies using copper chloride doses that ranged from 0 to 40 mg/kg BW (2×/wk, for 4 wk). Copper treated mice evidenced immunotoxicity as indicated by dose-related decreases and increases, respectively, in thymic and splenic weights. Histomorphological changes evidenced in these organs were thymic atrophy, white pulp shrinkage in the spleen, and apoptosis of splenocytes and thymocytes; these observations were confirmed by microscopic analyses. Cell count analyses indicated that the proliferative functions of the splenocytes and thymocytes were also altered because of the copper exposures. Among both cell types from the copper treated hosts, flow cytometric analyses revealed a dose related increase in the percentages of cells in the Sub-G₀/G₁ state, indicative of apoptosis which was further confirmed by Annexin V binding assay. In addition, the copper treatments altered the expression of selected cell death related genes such as EndoG and Bax in a dose related manner. Immunohistochemical analyses revealed that there was also increased ubiquitin expression in both the cell types. In conclusion, these studies show that sublethal exposure to copper (as copper chloride) induces toxicity in the thymus and spleen, and increased Sub G₀/G₁ population among splenocytes and thymocytes that is mediated, in part, by the EndoG-Bax-ubiquitin pathway. This latter damage to these cells that reside in critical immune system organs are likely to be important contributing factors underlying the immunosuppression that has been documented by other investigators following acute high dose/chronic low-medium dose exposures to copper agents.Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Research paper thumbnail of Splenocyte apoptosis in Plasmodium berghei ANKA infection: Possible Role of TNF- α and TGF- β

Cerebral malaria is associated with the circulating levels of tumour necrosis factor alpha (TNF-α... more Cerebral malaria is associated with the circulating levels of tumour necrosis factor alpha (TNF-α) and transforming growth factor β (TGF-β), but association between these two cytokines and implications in splenocyte apoptosis remain largely obscured. We have evaluated the outcome of TGF-β and TNF-α production in the context of splenocyte apoptosis during Plasmodium berghei ANKA (PbA) infection. Blood-stage PbA infection confirmed blood-brain barrier disruption, disarray of white pulp, increase in percentage of sub-G0/G1 and splenocyte apoptosis. Flow cytometric analysis reveals up-regulation of Fas-L followed by caspase-8 and caspase-3 activation and signifies possible involvement of Fas-L-mediated splenocyte apoptosis. We have observed down-regulation of TGF-β and up-regulation of TNF-α in tissue and serum level, respectively, during PbA infection. Association between the production of TGF-β and the severity of malaria infection in splenocytes was verified with TGF-β inhibitor that exacerbated the apoptotic process. In contrary, TNF-α inhibitor causes significant delay in apoptotic process, but could not alter the lethality of parasite. Thus, results from this study suggest that the critical balance between TGF-β and TNF-α might have a key role on Fas-L-mediated splenocyte apoptosis during experimental cerebral malaria.© 2012 Blackwell Publishing Ltd.