Kenneth Stapleford

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Office:

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Kenneth.Stapleford@stonybrook.edu

(631) 632-8818

(631) 632-9797

Arbovirus evolution, transmission, and pathogenesis.

Arthropod-borne viruses (arboviruses) are significant global public health threats. These viruses are transmitted to humans by arthropod vectors (mosquitoes, ticks, midges) and can lead to devastating outbreaks and severe disease. To date, there are limited or no antiviral therapies targeting these viruses. This problem is in large part due to our lack of fundamental knowledge regarding how arboviruses establish infections, replicate, and cause disease.

Our lab (opening July 2026) uses multidisciplinary in vitro (cell culture and organoids) and in vivo (animals and insects) approaches to dissect the fundamental mechanisms of viral transmission and pathogenesis. We focus on three major groups of human arboviruses: alphaviruses (chikungunya virus, mayaro virus), orthoflaviviruses (dengue virus, Zika virus), and orthobunyaviruses  (La Crosse virus, Oropouche virus) to understand the common and virus-specific mechanisms of disease. Several current projects in the lab are outlined below.

Mechanisms of entry and transmission: Arboviruses must infect humans and insects for a successful lifecycle. However, we understand little of the molecular mechanisms involved in virus entry and transmission. Here we focus on the viral class II fusion glycoproteins of alpha-, flavi-, and bunyaviruses to investigate how these individual viruses infect mammals and insect vectors. Moreover, in collaboration with the lab of Dr. Deigo Alvarez at the University of Buenos Aires (Argentina), we are developing novel antiviral compounds that block infection of diverse class II fusion protein containing viruses.

Virus evolution and replicase function: Arboviruses encode an error-prone RNA-dependent RNA polymerase (RdRp) that is critical for viral genome replication. The RdRp is responsible for robust viral evolution that drives outbreaks and epidemics. In these projects, we collaborate with Dr. Naide Azeredo at Fiocruz (Brazil) to study arbovirus evolution in humans. In addition, we use molecular biology and biochemistry to dissect the mechanisms of polymerase function at the level of replication complex assembly, RNA synthesis, and translation. Finally, in collaboration with Dr. Alan Talevi at the University of Buenos Aires (Argentina), we are developing new antivirals targeting the RdRp of multiple arboviruses in the hopes to block arbovirus infection.

Arbovirus pathogenesis and long-term complications: Arboviruses cause severe disease in humans, including chronic arthritis and encephalitis. However, our understanding of how these emerging viruses cause disease is not well-defined. Moreover, even after the viral infection is cleared, long-term sequelae can remain for months to years, yet we do not understand what is driving this post-infection disease. In these projects, we will use animal and organoid models to study how arboviruses establish infections, how they are cleared, and the long-term imprints they leave on infected individuals.

The insect vector: The insect vector is the last frontier in arbovirology. While we have begun to understand mammalian host factors and mechanisms that many viruses use for replication, our understanding of how the virus replicates in insects is poorly defined. In these projects, we are investigating the molecular mechanisms of how mosquito- and tick-borne pathogens replicate in insect vectors. We employ CRISPR-Cas9 screening systems in mosquito and tick cells to investigate how the host-pathogen interactions driving insect infection. In addition, we have an insectary where we can infect live mosquitoes and ticks to begin to understand how arboviruses evolve and are transmitted in insect models. 

A. Dedvukaj, NC. Rondeau, TJB. Vazquez, AE. Cristofalo, MV. Durawa, MC. Lutchko, KA. Stapleford. The La Crosse virus Gc head domain is a major determinant of infection and pathogenesis. J. Virol. 2025 Nov 25;99(11).

SN. Spector, MG. Noval, KA. Stapleford. Differential restriction of chikungunya virus in primary cardiac endothelial cells occurs at multiple steps in the viral life cycle. PLoS Negl Trop Dis. 2025 Mar 10;19(3).

MF. Martin, B. Bonaventure, NE. McCray, OB. Peersen, K. Rosen-Gagnon, KA. Stapleford. Distinct chikungunya virus polymerase palm subdomains contribute to viral protein accumulation and virion assembly. PLOS Pathogens. 2024 Oct 14;20(10).

SA. Thannickal, L. Battini, SN. Spector, MG. Noval, DE. Alvarez, KA. Stapleford. “Changes in the chikungunya virus E1 glycoprotein domain II and hinge influence E2 conformation, infectivity, and virus-receptor interactions.” J. Virol. 2024 Jul 23;98(7).

SA. Thannickal, SN. Spector, KA. Stapleford. “The La Crosse virus class II fusion glycoprotein ij loop contributes to infectivity and replication in vitro and in vivo.” J Virol. 2023 Aug 31;97(8).

MG. Noval, E. Bartnicki, SN. Spector, F. Izzo, P. Damani-Yokota, N. Narula, ST. Yeung, BA. Rodriguez-Rodriguez, MZ. Dewan, V. Mezzano, C. Loomis, KM. Khanna, KA. Stapleford. “MAVS signaling is required for preventing persistent chikungunya virus heart infection and chronic vascular tissue inflammation.” Nature Communications. 2023 Aug 3;14(1):4668.

MV. Rangel, N. McAllister, K. Dancel-Manning, MG. Noval, LA. Silva, KA. Stapleford. “Emerging chikungunya virus variants at the E1-E1 inter-glycoprotein spike interface impact virus attachment and Inflammation.” J. Virol. 2021 Dec 22.

MV. Rangel, N. Catanzaro, SA. Thannickal, KA. Crotty, MG. Noval, KEE. Johnson, E. Ghedin, HM. Lazear, KA. Stapleford. “Structurally conserved domains between flavivirus and alphavirus fusion glycoproteins contribute to replication in mammals and infection virion production.” J. Virol. 2021 Nov 10.