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DNA-free recombinant SV40 capsids protect mice from acute renal failure by inducing stress response, survival pathway
Veronika Butin-Israeli1, Dotan Uzi, Mahmoud Abd-El-Latif
1Department of Hematology, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Abstract:
Viruses induce signaling and host defense during infection. Employing these natural trigger mechanisms to combat organ or tissue failure is hampered by harmful effects of most viruses. Here we demonstrate that SV40 empty capsids (Virus Like Particles-VLPs), with no DNA, induce host Hsp/c70 and Akt-1 survival pathways, key players in cellular survival mechanisms. We postulated that this signaling might protect against organ damage in vivo. Acute kidney injury (AKI) was chosen as target. AKI is critical, prevalent disorder in humans, caused by nephrotoxic agents, sepsis or ischemia, via apoptosis/necrosis of renal tubular cells, with high morbidity and mortality. Systemic administration of VLPs activated Akt-1 and upregulated Hsp/c70 in vivo. Experiments in mercury-induced AKI mouse model demonstrated that apoptosis, oxidative stress and toxic renal failure were significantly attenuated by pretreatment with capsids prior to the mercury insult. Survival rate increased from 12% to >60%, with wide dose response. This study demonstrates that SV40 VLPs, devoid of DNA, may potentially be used as prophylactic agent for AKI. We anticipate that these finding may be projected to a wide range of organ failure, using empty capsids of SV40 as well as other viruses.
Insights
SV40 empty capsids (Virus Like Particles-VLPs) activate cellular survival pathways, protecting against acute kidney injury (AKI) in mice. This discovery offers a potential prophylactic strategy for organ damage, including AKI.
Area of Science:
- Virology
- Immunology
- Nephrology
Background:
- Viruses trigger host defense mechanisms, but their pathogenic nature limits therapeutic use.
- Cellular survival pathways, including Hsp/c70 and Akt-1, are crucial for mitigating organ damage.
- Acute kidney injury (AKI) is a prevalent and severe condition characterized by renal tubular cell death.
Purpose of the Study:
- To investigate if SV40 empty capsids (VLPs) can induce protective cellular signaling pathways.
- To evaluate the potential of SV40 VLPs as a prophylactic agent against AKI in vivo.
Main Methods:
- SV40 VLPs were administered systemically to mice.
- Activation of Hsp/c70 and Akt-1 pathways was assessed.
- A mercury-induced AKI mouse model was used to evaluate VLP efficacy.
- Apoptosis, oxidative stress, and survival rates were measured.
Main Results:
- Systemic VLP administration upregulated Hsp/c70 and activated Akt-1.
- Pretreatment with SV40 VLPs significantly attenuated mercury-induced apoptosis, oxidative stress, and renal failure.
- Survival rates in the AKI model increased from 12% to over 60% post-VLP pretreatment.
Conclusions:
- SV40 VLPs, devoid of genetic material, effectively induce protective host survival pathways.
- SV40 VLPs demonstrate significant prophylactic potential against AKI in a mouse model.
- These findings suggest broader applications for viral empty capsids in preventing various forms of organ failure.
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