Hantaviruses, escapees from the death row : viral mechanisms towards apoptosis resistance

Over the past decades, humanity has witnessed a constant stream of emerging pathogenic RNA viruses. The recurrent outbreaks of Ebola virus in Africa, the emergence of West Nile virus in North America and the sporadic but constant outbreaks of hantaviruses and arenaviruses are some examples of current public health concerns. Unravelling the strategies that these viruses use for immune evasion and for interference with the normal function of host cells remains of paramount importance in order to comprehend viral pathogenesis and ease the development of preventive measures and treatments.

Hantaviruses are worldwide-distributed zoonotic viruses that can cause spillover infections from rodents to humans. Human infection may develop into severe disease with high morbidity and case fatality rates of up to 40%. Despite continuous efforts, neither a vaccine nor specific treatments have been developed yet. Hantavirus-associated diseases appear to be immune-mediated and clinical manifestations relate to strong inflammation and vascular leakage. Although the precise mechanism of viral entry is still not well understood, endothelial cells represent the main target of hantaviruses. Despite the strong cytotoxic lymphocyte responses during acute disease, infected endothelial cells remain undamaged in hantavirus-infected patients. This puzzling observation has been partly explained by the capacity of pathogenic hantaviruses to inhibit the activity of caspase-3 and granzyme B, thereby blocking apoptosis (i.e. controlled cell suicide) in infected cells. The cellular pathways of apoptosis are multiple and represent highly complex and dynamic processes leading to heterogeneous outcomes. Such complexity echoes of course in the entangled mechanisms that some viruses use to sabotage apoptosis induction.

This thesis intends to recapitulate the current knowledge on how hantaviruses may cause pathogenesis in humans and further provides novel results on the capacity of hantaviruses to inhibit apoptosis, and on the interplay between these viruses and the host factor PCDH-1. In Paper I, we investigated if the anti-apoptotic characteristics previously reported for the pathogenic Andes and Hantaan hantaviruses were shared by other pathogenic and non-pathogenic hantaviruses. Second, since direct inhibition of caspase-3 and granzyme B by hantaviruses can only partly explain the strong viral-mediated inhibition of apoptosis, in Paper II and Paper III we sought to further unravel the mechanisms behind viral resistance to chemically-induced apoptosis (Paper II), and to TRAIL-mediated killing of infected cells (Paper III). PCDH-1 is an important cell entry factor for American hantaviruses and PCDH-1 knock out significantly reduced hantavirus infectivity and pathogenesis in an animal model, showing that targeting of PCDH-1 could provide strategies to hamper infection and disease caused by some hantaviruses. In Paper IV, we examined the role of PCDH-1 in entry and replication of the European Puumala hantavirus. As a whole, the work here presented aims at better understanding the mechanisms of hantavirus replication and pathogenesis in humans.

List of scientific papers

I. Carles Solà-Riera, Shawon Gupta, Hans-Gustaf Ljunggren, and Jonas Klingström. Orthohantaviruses belonging to three distinct phylogroups all inhibit apoptosis in infected target cells. Sci Rep. 2019. 9(1):834.
https://doi.org/10.1038/s41598-018-37446-1

II. Carles Solà-Riera and Jonas Klingström. Hantavirus inhibits apoptosis by preventing mitochondrial membrane potential loss through up-regulation of the pro-survival factor BCL-2. [Manuscript]

III. Carles Solà-Riera, Shawon Gupta, Kimia T. Maleki, Patricia González-Rodriguez, Dalel Saidi, Christine L. Zimmer, Sindhu Vangeti, Laura Rivino, Yee-Sin Leo, David Chien Lye, Paul A. MacAry, Clas Ahlm, Anna Smed-Sörensen, Bertrand Joseph, Niklas K. Björkström, Hans-Gustaf Ljunggren, and Jonas Klingström. Hantavirus Inhibits TRAIL-Mediated Killing of Infected Cells by Downregulating Death Receptor 5. Cell Rep. 2019. 28(8):2124-2139.
https://doi.org/10.1016/j.celrep.2019.07.066

IV. Carles Solà-Riera, Mirte N. Pascha, Marina Garcia, Rohit K. Jangra, Eva Mittler, Hans-Gustaf Ljunggren, Kartik Chandran, and Jonas Klingström. Possible dual role for PCDH-1 in the replication cycle of Puumala virus. [Manuscript]