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Zika researcher Saguna Verma gets new funding, forges cross-country collaboration to learn why the virus can hide and linger in men

Date: June 11th, 2018 in JABSOM News    Print or PDF

Dr. Verma is pictured

Pictured: Dr. Saguna Verma. Amanda Shell photo.

By Tina Shelton JABSOM Communications Director

University of Hawaiʻi-Mānoa (UHM) Zika researcher Dr. Saguna Verma has received nearly half a million dollars in new funding to extend her research into how the virus can hide in men’s bodies for months after they are infected, posing a risk that their sexual partners can be stricken. There already have been more than 42,000 cases of Zika in the United States, and it remains a serious threat to places — including Hawaiʻi — where the mosquito determined to carry and spread Zika thrives.

But beyond mosquitos, Dr. Verma and her team are especially concerned about how humans can spread the disease, particularly men who may think any illness they suffered — if they experienced symptoms — is long passed.

“As many as 56% of men still had the Zika virus in their seminal fluid for months after the virus had cleared other body fluids,” said Dr. Verma, with the UHM John A. Burns School of Medicine (JABSOM) Department of Tropical Medicine, Microbiology and Pharmacology. “That suggests the ability of the Zika virus to enter into the testes to establish persistent infection.” That is alarming because typically, the testes, so vital in reproduction, enjoy immunity from other viral infections.

Using cells made to resemble the testes by collaborators at North Carolina’s Wake Forest University, Verma’s research team hopes to find a way to prevent Zika from breaking through immune barriers that normally stop viruses from infecting male reproductive organs.

“I believe that the key to curing testicular infection of viruses will be to know how the testes looses its unique immune privilege position in the human body,” explained Dr. Verma. “It is only when we understand the complexities of the interaction between the testis and testes-tropic viruses, that we will be able to develop strategies and therapies to prevent or clear the infection quickly.”

The new funding, $484,750, is from the National Institutes of Health and the Hawaiʻi Community Foundation.

The Verma team has already shown that the lengthy “gatekeeper” cells that protect sperm cells (known as Sertoli cells) succumb easily to Zika virus infection. Now, her team will use cells made to resemble the testes to see exactly how the cells respond to the virus, and discern key pathways uniquely associated with testicular immune response and germ cell survival.

“I believe that the key to curing testicular infection of viruses will be to know how the testes looses its unique immune privilege position in the human body,” explained Dr. Saguna Verma. “It is only when we understand the complexities of the interaction between the testis and testes-tropic viruses, that we will be able to develop strategies and therapies to prevent or clear the infection quickly.”

Novel Zika testing model created in the laboratory
Dr. Verma said the testes seem to be a particularly understudied area among immune-privileged sites, which also include the eye and the brain. Human testes are less readily available than other tissue types donated to research, making it tough to validate findings observed in animal models. However, Dr. Verma’s group initiated a new collaboration with clinician-researchers with at the Wake Forest School of Medicine in Winston-Salem, NC, who have expertise in tissue re-engineering. The researchers are establishing Zika virus infections in organoids derived from human cells that mimic the structure and function of human testes. (The human 3D testicular organoid (HTO) culture system uses cells present in the interstitial space (testosterone producing LCs), seminiferous tubules (SCs, peritubular cells and spermatogonia) and a human testes extracellular matrix that supports differentiation of haploid spermatocytes.)

Dr. Verma’s preliminary studies demonstrate that the Zika virus can productively infect these model testes.

“We anticipate that the data from this study will fill the fundamental gap of knowledge about the cell types that allow for the long-term replication of Zika virus in the testes, and enhance our understanding of the unique immune response to testicular virus infection.”

About Zika
The 2015-2016 epidemic of the Zika virus caused severe unexpected clinical outcomes including the disabling birth defects (microcephaly) and a severe and progressive neurological disorder (Guillain-Barré Syndrome). ZIKV is primarily a mosquito-transmitted virus but the concerns regarding sexual transmission has gained urgency as the alarming increase in the number of cases of microcephaly in ZIKV-infected women coincided with the detection of the virus in the semen.

Hawaiʻi has not had a locally-acquired case of Zika, but people here are vulnerable, because our state has the same type of mosquitos that have a proven ability to spread the virus should they bite an infected person.

Learn more about Zika from the Centers for Disease Control (CDC).

Funding details
National Institutes of Health:
1R21AI140248-01
(Saguna Verma-05/18/2018-04/30/2020)
Project Title: Human 3D testicular organoids as a model to dissect cell-type specific tropism and immune response to Zika virus
Total Cost: $437,750

Hawaiʻi Community Foundation:
(Saguna Verma-06/01/2018-12/31/2019)
Project Title: AXL Receptor Regulates Zika Virus Entry and Immune Response in Human Testicular Cells.
Total Cost: $47,000

Recent ZIKV Publications
Siemann DS, Strange DP, Maharaj PM, Shi P-Y andVerma S. Zika virus infects human Sertoli cells 
and modulates the integrity of the in vitro blood-testis barrier model. Journal of Virology 2017, 27;91(22) doi: 10.1128/JVI.00623-17. https://www-ncbi-nlm-nih-gov.eres.library.manoa.hawaii.edu/pubmed/28878076

Strange DP, Zarandi NP, Trivedi G, Atala A, Bishop CE, Sadri-Ardekani H, and Verma S. Human testicular organoids as a novel tool to study Zika virus pathogenesis. Emerging Microbes and Infection 2018 May 9;7(1):82. doi: 10.1038/s41426-018-0080-7.https://www-ncbi-nlm-nih-gov.eres.library.manoa.hawaii.edu/pubmed/29739931

Strange DP, Siemann DS, Green R, Belcaid, M, Gale Jr. M and Verma S. Transcriptome analysis of primary human Sertoli cells infected with Zika virus reveals unique insights into host-pathogen cross 
talk. Scientific Reports (In press) 


Book Chapter
G Kaur, K Wright, S Verma, A Haynes, JM Dufour. The good, bad and ugly of testicular immune privilege published in ‘Molecular mechanisms in Spermatogenesis’ (In press, Publisher: Springer Nature)

Link to positive comments made by the editor of Nature Medicine about the Verma team’s research.

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