Leishmania donovani Inhibitor of Serine Peptidases 2 Mediated Inhibition of Lectin Pathway and Upregulation of C5aR Signaling Promote Parasite Survival inside Host
Leishmania donovani, the causative agent of Indian visceral leishmaniasis has to face several barriers of the immune system inside the mammalian host for its survival. The complement system is one of the first barriers and consists of a well-balanced network of proteases including S1A family serine...
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Frontiers Media S.A.
2018-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fimmu.2018.00063/full |
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| author | Sudha Verma Abhishek Mandal Md. Yousuf Ansari Ajay Kumar Kumar Abhishek Ayan Kumar Ghosh Ashish Kumar Vinod Kumar Sushmita Das Pradeep Das |
| author_facet | Sudha Verma Abhishek Mandal Md. Yousuf Ansari Ajay Kumar Kumar Abhishek Ayan Kumar Ghosh Ashish Kumar Vinod Kumar Sushmita Das Pradeep Das |
| author_sort | Sudha Verma |
| collection | DOAJ |
| description | Leishmania donovani, the causative agent of Indian visceral leishmaniasis has to face several barriers of the immune system inside the mammalian host for its survival. The complement system is one of the first barriers and consists of a well-balanced network of proteases including S1A family serine proteases (SPs). Inhibitor of serine peptidases (ISPs) is considered as inhibitor of S1A family serine peptidases and is reported to be present in trypanosomes, including Leishmania. In our previous study, we have deciphered the role of ISPs [LdISP1 and L. donovani inhibitor of serine peptidases 2 (LdISP2)] in the survival of L. donovani inside the sandfly midgut. However, the role of theses ISPs in the survival of L. donovani inside mammalian host still remains elusive. In the present study, we have deciphered the inhibitory effect of LdISPs on the host complement S1A serine peptidases, such as C1r/C1s and MASP1/MASP2. Our study suggested that although both rLdISP1 and rLdISP2 inferred strong interaction with C1complex and MBL-associated serine proteases (MASPs) but rLdISP2 showed the stronger inhibitory effect on MASP2 than rLdISP1. Moreover, we found that rLdISP2 significantly reduces the formation of C3, C5 convertase, and membrane attacking complex (MAC) by lectin pathway (LP) resulting in significant reduction in serum mediated lysis of the parasites. The role of LdISP2 on neutrophil elastase-mediated C5aR signaling was also evaluated. Notably, our results showed that infection of macrophages with ISP2-overexpressed Leishmania parasites significantly induces the expression of C5aR both at the transcript and translational level. Simultaneously, infection with ISP2KD parasites results in downregulation of host PI3K/AKT phosphorylation and increased in IL-12 production. Taken together, our findings clearly suggest that LdISP2 promotes parasite survival inside host by inhibiting MAC formation and complement-mediated lysis via LP and by upregulation of C5aR signaling. |
| first_indexed | 2024-12-11T03:30:44Z |
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| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-11T03:30:44Z |
| publishDate | 2018-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj.art-c2e8613a0c694700ae2e9a0b29e2ecbc2022-12-22T01:22:24ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-01-01910.3389/fimmu.2018.00063313648Leishmania donovani Inhibitor of Serine Peptidases 2 Mediated Inhibition of Lectin Pathway and Upregulation of C5aR Signaling Promote Parasite Survival inside HostSudha Verma0Abhishek Mandal1Md. Yousuf Ansari2Ajay Kumar3Kumar Abhishek4Ayan Kumar Ghosh5Ashish Kumar6Vinod Kumar7Sushmita Das8Pradeep Das9Department of Molecular Biology, Rajendra Memorial Research Institute of Medical Sciences (ICMR), Patna, IndiaDepartment of Molecular Biology, Rajendra Memorial Research Institute of Medical Sciences (ICMR), Patna, IndiaMM College of Pharmacy, Maharishi Markandeshwar University, Ambala, IndiaDepartment of Molecular Biology, Rajendra Memorial Research Institute of Medical Sciences (ICMR), Patna, IndiaDepartment of Molecular Biology, Rajendra Memorial Research Institute of Medical Sciences (ICMR), Patna, IndiaDepartment of Molecular Biology, Rajendra Memorial Research Institute of Medical Sciences (ICMR), Patna, IndiaDepartment of Molecular Biology, Rajendra Memorial Research Institute of Medical Sciences (ICMR), Patna, IndiaDepartment of Molecular Biology, Rajendra Memorial Research Institute of Medical Sciences (ICMR), Patna, IndiaDepartment of Microbiology, All India Institute of Medical Sciences, Patna, IndiaDepartment of Molecular Biology, Rajendra Memorial Research Institute of Medical Sciences (ICMR), Patna, IndiaLeishmania donovani, the causative agent of Indian visceral leishmaniasis has to face several barriers of the immune system inside the mammalian host for its survival. The complement system is one of the first barriers and consists of a well-balanced network of proteases including S1A family serine proteases (SPs). Inhibitor of serine peptidases (ISPs) is considered as inhibitor of S1A family serine peptidases and is reported to be present in trypanosomes, including Leishmania. In our previous study, we have deciphered the role of ISPs [LdISP1 and L. donovani inhibitor of serine peptidases 2 (LdISP2)] in the survival of L. donovani inside the sandfly midgut. However, the role of theses ISPs in the survival of L. donovani inside mammalian host still remains elusive. In the present study, we have deciphered the inhibitory effect of LdISPs on the host complement S1A serine peptidases, such as C1r/C1s and MASP1/MASP2. Our study suggested that although both rLdISP1 and rLdISP2 inferred strong interaction with C1complex and MBL-associated serine proteases (MASPs) but rLdISP2 showed the stronger inhibitory effect on MASP2 than rLdISP1. Moreover, we found that rLdISP2 significantly reduces the formation of C3, C5 convertase, and membrane attacking complex (MAC) by lectin pathway (LP) resulting in significant reduction in serum mediated lysis of the parasites. The role of LdISP2 on neutrophil elastase-mediated C5aR signaling was also evaluated. Notably, our results showed that infection of macrophages with ISP2-overexpressed Leishmania parasites significantly induces the expression of C5aR both at the transcript and translational level. Simultaneously, infection with ISP2KD parasites results in downregulation of host PI3K/AKT phosphorylation and increased in IL-12 production. Taken together, our findings clearly suggest that LdISP2 promotes parasite survival inside host by inhibiting MAC formation and complement-mediated lysis via LP and by upregulation of C5aR signaling.http://journal.frontiersin.org/article/10.3389/fimmu.2018.00063/fullISP2MBL-associated serine proteasesmembrane attacking complexserine proteasesLeishmaniaPI3K |
| spellingShingle | Sudha Verma Abhishek Mandal Md. Yousuf Ansari Ajay Kumar Kumar Abhishek Ayan Kumar Ghosh Ashish Kumar Vinod Kumar Sushmita Das Pradeep Das Leishmania donovani Inhibitor of Serine Peptidases 2 Mediated Inhibition of Lectin Pathway and Upregulation of C5aR Signaling Promote Parasite Survival inside Host Frontiers in Immunology ISP2 MBL-associated serine proteases membrane attacking complex serine proteases Leishmania PI3K |
| title | Leishmania donovani Inhibitor of Serine Peptidases 2 Mediated Inhibition of Lectin Pathway and Upregulation of C5aR Signaling Promote Parasite Survival inside Host |
| title_full | Leishmania donovani Inhibitor of Serine Peptidases 2 Mediated Inhibition of Lectin Pathway and Upregulation of C5aR Signaling Promote Parasite Survival inside Host |
| title_fullStr | Leishmania donovani Inhibitor of Serine Peptidases 2 Mediated Inhibition of Lectin Pathway and Upregulation of C5aR Signaling Promote Parasite Survival inside Host |
| title_full_unstemmed | Leishmania donovani Inhibitor of Serine Peptidases 2 Mediated Inhibition of Lectin Pathway and Upregulation of C5aR Signaling Promote Parasite Survival inside Host |
| title_short | Leishmania donovani Inhibitor of Serine Peptidases 2 Mediated Inhibition of Lectin Pathway and Upregulation of C5aR Signaling Promote Parasite Survival inside Host |
| title_sort | leishmania donovani inhibitor of serine peptidases 2 mediated inhibition of lectin pathway and upregulation of c5ar signaling promote parasite survival inside host |
| topic | ISP2 MBL-associated serine proteases membrane attacking complex serine proteases Leishmania PI3K |
| url | http://journal.frontiersin.org/article/10.3389/fimmu.2018.00063/full |
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