NDLI: IL-4 contributes to failure, and colludes with IL-10 to exacerbate Leishmania donovani infection following administration of a subcutaneous leishmanial antigen vaccine

Content Provider	Springer Nature : BioMed Central
Author	Bhowmick, Sudipta Ravindran, Rajesh Ali, Nahid
Abstract	Background Visceral leishmaniasis caused by the protozoan parasite Leishmania donovani complex is a potentially fatal disease if left untreated. Few treatment options exist and are toxic, costly and ineffective against resistant strains. Thus a safe and efficacious vaccine to combat this disease is needed. Previously, we reported that intraperitoneal administration of leishmanial antigens (LAg) entrapped in liposomes conferred protection to BALB/c mice against L. donovani challenge infection. However, this vaccine failed to protect mice when administered subcutaneously. We therefore evaluated whether formulation of LAg in combination with two commonly used human-compatible adjuvants, alum and saponin, could improve the protective efficacy of subcutaneously administered LAg, to a level comparable to that of the intraperitoneal liposomal vaccination. Results Vaccine formulations of LAg with alum or saponin failed to reduce parasite burden in the liver, and alum + LAg immunized mice also failed to reduce parasite burden in the spleen. Interestingly, saponin + LAg vaccination actually resulted in an increased L. donovani parasitic load in the spleen following L. donovani challenge, suggesting this regimen exacerbates the infection. In contrast, mice immunized intraperitoneally with Lip + LAg demonstrated significant protection in both liver and spleen, as expected. Mechanistically, we found that failure of alum + LAg to protect mice was associated with elevated levels of IL-4, whereas both IL-4 and IL-10 levels were increased in saponin + LAg immunized mice. This outcome served to exacerbate L. donovani infection in the saponin + LAg group, despite a concurrent increase in proinflammatory IFN-γ production. On the contrary, protection against L. donovani challenge in Lip + LAg immunized mice was associated with elevated levels of IFN-γ in conjunction with low levels of IL-4 and IL-10 production. Conclusions These findings indicate that elevated levels of IL-4 may contribute to LAg vaccine failure, whereas combined elevation of IL-4 together with IL-10 exacerbated the disease as observed in saponin + LAg immunized mice. In contrast, a robust IFN-γ response, in the absence of IL-4 and IL-10 production, was associated with protective immunity following administration of the Lip + LAg vaccine. Together these findings suggest that optimization of antigen/adjuvant formulations to minimize IL-4 and IL-10 induction may be helpful in the development of high efficacy vaccines targeting Leishmania.
Related Links	https://bmcmicrobiol.biomedcentral.com/counter/pdf/10.1186/1471-2180-14-8.pdf
Ending Page	12
Page Count	12
Starting Page	1
File Format	HTM / HTML
ISSN	14712180
DOI	10.1186/1471-2180-14-8
Journal	BMC Microbiology
Issue Number	1
Volume Number	14
Language	English
Publisher	BioMed Central
Publisher Date	2014-01-15
Access Restriction	Open
Subject Keyword	Microbiology Biological Microscopy Mycology Parasitology Virology Life Sciences Leishmania donovani Alum Saponin IL-4 IL-10
Content Type	Text
Resource Type	Article
Subject	Microbiology Microbiology (medical)
Journal Impact Factor	4/2023
5-Year Journal Impact Factor	4.6/2023

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