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Host response profile of human brain proteome in toxoplasma encephalitis co-infected with HIV.

Sahu A, Kumar S, Sreenivasamurthy SK, Selvan LD, Madugundu AK, Yelamanchi SD, Puttamallesh VN, Dey G, Anil AK, Srinivasan A, Mukherjee KK, Gowda H, Satishchandra P, Mahadevan A, Pandey A, Prasad TS, Shankar SK - Clin Proteomics (2014)

Bottom Line: Primary infection with T. gondii in immunocompetent individuals remains largely asymptomatic.In contrast, in immunocompromised individuals, reactivation of the parasite results in severe complications and mortality.Molecular pathways identified to be associated with the disease should enhance our understanding of pathogenesis in toxoplasma encephalitis.

View Article: PubMed Central - PubMed

Affiliation: Institute of Bioinformatics, International Technology Park, Bangalore, 560066 India ; Bioinformatics Centre, School of Life Sciences, Pondicherry University, Puducherry, 605014 India.

ABSTRACT

Background: Toxoplasma encephalitis is caused by the opportunistic protozoan parasite Toxoplasma gondii. Primary infection with T. gondii in immunocompetent individuals remains largely asymptomatic. In contrast, in immunocompromised individuals, reactivation of the parasite results in severe complications and mortality. Molecular changes at the protein level in the host central nervous system and proteins associated with pathogenesis of toxoplasma encephalitis are largely unexplored. We used a global quantitative proteomic strategy to identify differentially regulated proteins and affected molecular networks in the human host during T. gondii infection with HIV co-infection.

Results: We identified 3,496 proteins out of which 607 proteins were differentially expressed (≥1.5-fold) when frontal lobe of the brain from patients diagnosed with toxoplasma encephalitis was compared to control brain tissues. We validated differential expression of 3 proteins through immunohistochemistry, which was confirmed to be consistent with mass spectrometry analysis. Pathway analysis of differentially expressed proteins indicated deregulation of several pathways involved in antigen processing, immune response, neuronal growth, neurotransmitter transport and energy metabolism.

Conclusions: Global quantitative proteomic approach adopted in this study generated a comparative proteome profile of brain tissues from toxoplasma encephalitis patients co-infected with HIV. Differentially expressed proteins include previously reported and several new proteins in the context of T. gondii and HIV infection, which can be further investigated. Molecular pathways identified to be associated with the disease should enhance our understanding of pathogenesis in toxoplasma encephalitis.

No MeSH data available.


Related in: MedlinePlus

Biological network analysis of differentially expressed proteins using GeneSpring identified deregulated BDNF pathway: Nineteen proteins involved in the BDNF pathway were differentially expressed including the downregulation of the BDNF receptor protein – NTRK2. Proteins involved in BDNF mediated lamellipodia formation and neurite outgrowth were downregulated whereas proteins involved in BDNF mediated synaptic plasticity were overexpressed.
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Fig3: Biological network analysis of differentially expressed proteins using GeneSpring identified deregulated BDNF pathway: Nineteen proteins involved in the BDNF pathway were differentially expressed including the downregulation of the BDNF receptor protein – NTRK2. Proteins involved in BDNF mediated lamellipodia formation and neurite outgrowth were downregulated whereas proteins involved in BDNF mediated synaptic plasticity were overexpressed.

Mentions: Pathway analysis of the differentially expressed proteins in TE co-infected with HIV brain tissue samples using the Pathway Architect module in GeneSpring (version 12.6) revealed the enrichment of several proteins involved in pathways such as neural transmission across chemical synapse, neurotransmitter release cycle, antigen processing and presentation along with complement and coagulation cascade pathway. In addition, several key modulators of the brain-derived neurotrophic factor (BDNF) signaling pathway were found to be differentially regulated, including aldo-keto reductase (AKR1C1), alkaline phosphatase (ALPL), secreted phosphoprotein (SPP1), heat shock protein (HSPA1A), chromogranin B (CHGB), ras homolog family member (RHOG), regulating synaptic membrane exocytosis (RIMS3), inositol polyphosphate-1-phosphatase (INPP1), integrin, alpha 2 (ITGA2), filamin C (FLNC) and polymerase I transcript release factor (PTRF) [17]. RHOG, which was found to be downregulated in TE compared to control tissues, is involved in mediating BDNF-induced neurite outgrowth [18]. It has been reported that HIV-1 promotes neuronal injury by reducing the length of neuronal processes through reduction in the mature BDNF levels in neurons [19]. Therefore, differential expression of several important molecules in BDNF signaling pathway may be the cause of cognitive aberration in HIV-associated TE (Figure 3).Figure 3


Host response profile of human brain proteome in toxoplasma encephalitis co-infected with HIV.

Sahu A, Kumar S, Sreenivasamurthy SK, Selvan LD, Madugundu AK, Yelamanchi SD, Puttamallesh VN, Dey G, Anil AK, Srinivasan A, Mukherjee KK, Gowda H, Satishchandra P, Mahadevan A, Pandey A, Prasad TS, Shankar SK - Clin Proteomics (2014)

Biological network analysis of differentially expressed proteins using GeneSpring identified deregulated BDNF pathway: Nineteen proteins involved in the BDNF pathway were differentially expressed including the downregulation of the BDNF receptor protein – NTRK2. Proteins involved in BDNF mediated lamellipodia formation and neurite outgrowth were downregulated whereas proteins involved in BDNF mediated synaptic plasticity were overexpressed.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4232683&req=5

Fig3: Biological network analysis of differentially expressed proteins using GeneSpring identified deregulated BDNF pathway: Nineteen proteins involved in the BDNF pathway were differentially expressed including the downregulation of the BDNF receptor protein – NTRK2. Proteins involved in BDNF mediated lamellipodia formation and neurite outgrowth were downregulated whereas proteins involved in BDNF mediated synaptic plasticity were overexpressed.
Mentions: Pathway analysis of the differentially expressed proteins in TE co-infected with HIV brain tissue samples using the Pathway Architect module in GeneSpring (version 12.6) revealed the enrichment of several proteins involved in pathways such as neural transmission across chemical synapse, neurotransmitter release cycle, antigen processing and presentation along with complement and coagulation cascade pathway. In addition, several key modulators of the brain-derived neurotrophic factor (BDNF) signaling pathway were found to be differentially regulated, including aldo-keto reductase (AKR1C1), alkaline phosphatase (ALPL), secreted phosphoprotein (SPP1), heat shock protein (HSPA1A), chromogranin B (CHGB), ras homolog family member (RHOG), regulating synaptic membrane exocytosis (RIMS3), inositol polyphosphate-1-phosphatase (INPP1), integrin, alpha 2 (ITGA2), filamin C (FLNC) and polymerase I transcript release factor (PTRF) [17]. RHOG, which was found to be downregulated in TE compared to control tissues, is involved in mediating BDNF-induced neurite outgrowth [18]. It has been reported that HIV-1 promotes neuronal injury by reducing the length of neuronal processes through reduction in the mature BDNF levels in neurons [19]. Therefore, differential expression of several important molecules in BDNF signaling pathway may be the cause of cognitive aberration in HIV-associated TE (Figure 3).Figure 3

Bottom Line: Primary infection with T. gondii in immunocompetent individuals remains largely asymptomatic.In contrast, in immunocompromised individuals, reactivation of the parasite results in severe complications and mortality.Molecular pathways identified to be associated with the disease should enhance our understanding of pathogenesis in toxoplasma encephalitis.

View Article: PubMed Central - PubMed

Affiliation: Institute of Bioinformatics, International Technology Park, Bangalore, 560066 India ; Bioinformatics Centre, School of Life Sciences, Pondicherry University, Puducherry, 605014 India.

ABSTRACT

Background: Toxoplasma encephalitis is caused by the opportunistic protozoan parasite Toxoplasma gondii. Primary infection with T. gondii in immunocompetent individuals remains largely asymptomatic. In contrast, in immunocompromised individuals, reactivation of the parasite results in severe complications and mortality. Molecular changes at the protein level in the host central nervous system and proteins associated with pathogenesis of toxoplasma encephalitis are largely unexplored. We used a global quantitative proteomic strategy to identify differentially regulated proteins and affected molecular networks in the human host during T. gondii infection with HIV co-infection.

Results: We identified 3,496 proteins out of which 607 proteins were differentially expressed (≥1.5-fold) when frontal lobe of the brain from patients diagnosed with toxoplasma encephalitis was compared to control brain tissues. We validated differential expression of 3 proteins through immunohistochemistry, which was confirmed to be consistent with mass spectrometry analysis. Pathway analysis of differentially expressed proteins indicated deregulation of several pathways involved in antigen processing, immune response, neuronal growth, neurotransmitter transport and energy metabolism.

Conclusions: Global quantitative proteomic approach adopted in this study generated a comparative proteome profile of brain tissues from toxoplasma encephalitis patients co-infected with HIV. Differentially expressed proteins include previously reported and several new proteins in the context of T. gondii and HIV infection, which can be further investigated. Molecular pathways identified to be associated with the disease should enhance our understanding of pathogenesis in toxoplasma encephalitis.

No MeSH data available.


Related in: MedlinePlus