About

Vaithilingaraja Arumugaswami is a professor in the Department of Pharmacology at the University of California, Los Angeles. His laboratory focuses on understanding the pathogenic mechanisms of viruses in the Flaviviridae family, including Hepatitis C Virus, Zika Virus, and Dengue Virus. His research addresses the global health risks posed by these viruses, which are transmitted through mosquito vectors and contact with contaminated blood and bodily fluids. A major area of his work involves developing a potent recombinant vaccine to prevent Zika virus infection, utilizing reverse genetics systems to engineer attenuating mutations in the viral genome and testing these in animal models for safety and immunological profiles. Additionally, he investigates the impact of different modes of Zika virus transmission on fetal outcomes, employing human pluripotent stem cell-derived ocular progenitor cells and 3D optic cup organoids to model congenital eye disease caused by Zika. His research also explores the molecular and genetic basis of cellular perturbations induced by Zika virus, aiming to understand eye development and identify therapeutic interventions. Furthermore, he is developing a recombinant Zika virus-based immuno-oncolytic therapy targeting glioblastoma, proposing that oncolytic virus therapy can enhance immune responses against solid tumors like glioblastoma, which currently has a median survival of 12 to 15 months following diagnosis.

Research topics

• Biology
• Medicine
• Virology
• Immunology
• Genetics
• Cell biology
• Internal medicine
• Pathology
• Bioinformatics
• Cancer research
• Pharmacology
• Biochemistry

Selected publications

• B Cell Receptor’s function in virus entry: Anti-SARS-CoV-2 B cell receptors can mediate viral entry in an ACE2-independent mechanism

  PLoS Pathogens · 2026-02-06

  articleOpen access

  B cells play a crucial role in humoral immunity, acting as sentinels against viral infections by using their B cell receptors (BCRs) to recognize viral proteins. This recognition typically triggers a response leading to the production of neutralizing antibodies against viral surface proteins, such as the viral envelope proteins. However, recent studies have revealed a surprising dual role for BCRs, showing that some enveloped viruses and viral vectors, such as Dengue virus and lentiviral vectors, can exploit anti-viral BCRs as their attachment and entry receptors to infect/transduce B cells. While these viruses use a simple low-pH-dependent fusion mechanism for entry, it remained unclear whether BCRs could facilitate the entry of viruses with more complex fusion requirements, such as HIV-1 and SARS-CoV-2, which rely on their cognate receptors to activate their fusion machinery. In this study, we investigated the ability of BCRs to mediate viral entry for HIV-1 and SARS-CoV-2, which require specific host receptors (CD4 and ACE2, respectively) to activate their fusion machinery. We found that while anti-HIV-1 envelope protein BCRs can mediate viral attachment, they are unable to facilitate viral fusion and entry. In contrast, anti-SARS-CoV-2 Spike (S) protein BCRs not only mediate attachment but also enable viral entry in the absence of the ACE2 receptor. Our findings demonstrate that the ability of anti-viral BCRs to mediate viral fusion/entry is not universal but depends on the specific viral envelope protein. This novel entry pathway has important implications for both viral replication and the development of B cell-mediated immunity.

  PublisherDOI

• Differential tropisms of old and new world hantaviruses influence virulence and developing host-directed antiviral candidates

  PLoS Pathogens · 2025-08-26 · 2 citations

  articleOpen accessSenior authorCorresponding

  Hantaviruses are zoonotically transmitted from rodents to humans through the respiratory route, with no currently approved antivirals or widely available vaccines. The recent discovery of interhuman-transmitted Andes virus (ANDV) necessitates the systematic identification of cell tropism, infective potential, and potent therapeutic agents. We utilized human primary lung endothelial cells, various pluripotent stem cell-derived heart and brain cell types, and established human lung organoid models to evaluate the tropisms of Old World Hantaan (HTNV) and New World ANDV and Sin Nombre (SNV) viruses. ANDV exhibited broad tropism for all cell types assessed. SNV readily infected pulmonary endothelial cells, while HTNV robustly amplified in endothelial cells, cardiomyocytes, and astrocytes. We also provide the first evidence of hantaviral infection in human 3D distal lung organoids, which effectively modeled these differential tropisms. ANDV infection transcriptionally promoted cell injury and inflammatory responses, and downregulated lipid metabolic pathways in lung epithelial cells. Evaluation of selected drug candidates and pharmacotranscriptomics revealed that the host-directed small molecule compound urolithin B inhibited ANDV infection and restored cellular metabolism with minimal changes in host transcription. Given the scarcity of academic BSL-4 facilities that enable in vivo hantaviral studies, this investigation presents advanced human cell-based model systems that closely recapitulate host cell tropism and responses to infection, thereby providing critical platforms to evaluate potential antiviral drug candidates.

  PublisherOA PDFDOI

• Drug screen reveals new potent host-targeted antivirals against Mpox virus

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-07 · 2 citations

  preprintOpen accessSenior authorCorresponding

  Mpox virus (MPXV), a re-emerging zoonotic threat, has caused outbreaks in non-endemic regions through respiratory, sexual, and close-contact transmission. The increased transmissibility of Clade IIb fueled the 2022 global outbreak, with 2024 Clade Ib spread in the Democratic Republic of Congo further escalating concern. Both outbreaks were declared public health emergencies by the WHO. Although tecovirimat (TPOXX) has been used off-label for Mpox, its limited effectiveness highlights the critical need for newer antivirals for MPXV. We conducted high-throughput antiviral drug screening using a host-directed kinase inhibitor library composed of 2,750 compounds against 2022 Clade IIb MPXV. Our primary screen identified 138 compounds preventing MPXV cytopathic effects, including multiple inhibitors of EGFR, PI3K-mTOR, and Ras/Raf, as well as apoptosis and autophagy regulators. Secondary and tertiary screenings yielded a shortlist of potent, nontoxic antiviral compounds that inhibited MPXV replication. Three selected compounds, IRAK4-IN-6, SM-7368, and KRAS inhibitor-10, reduced MPXV-induced cell death in primary human epidermal keratinocytes. IRAK4-IN-6 and SM-7368 were also found to modulate NF-κB and STING signaling. Furthermore, these compounds were found effective in reducing skin lesions and viral burden in a mouse model of MPXV skin infection. Together, our study reveals new classes of antiviral compounds against MPXV, offering promising candidates for future clinical development.

  PublisherOA PDFDOI

• Optimization of a micro-scale air–liquid-interface model of human proximal airway epithelium for moderate throughput drug screening for SARS-CoV-2

  Respiratory Research · 2025-01-16 · 3 citations

  articleOpen access

  BACKGROUND: Many respiratory viruses attack the airway epithelium and cause a wide spectrum of diseases for which we have limited therapies. To date, a few primary human stem cell-based models of the proximal airway have been reported for drug discovery but scaling them up to a higher throughput platform remains a significant challenge. As a result, most of the drug screening assays for respiratory viruses are performed on commercial cell line-based 2D cultures that provide limited translational ability. METHODS: We optimized a primary human stem cell-based mucociliary airway epithelium model of SARS-CoV-2 infection, in 96-well air-liquid-interface (ALI) format, which is amenable to moderate throughput drug screening. We tested the model against SARS-CoV-2 parental strain (Wuhan) and variants Beta, Delta, and Omicron. We applied this model to screen 2100 compounds from targeted drug libraries using a high throughput-high content image-based quantification method. RESULTS: The model recapitulated the heterogeneity of infection among patients with SARS-CoV-2 parental strain and variants. While there were heterogeneous responses across variants for host factor targeting compounds, the two direct-acting antivirals we tested, Remdesivir and Paxlovid, showed consistent efficacy in reducing infection across all variants and donors. Using the model, we characterized a new antiviral drug effective against both the parental strain and the Omicron variant. CONCLUSION: This study demonstrates that the 96-well ALI model of primary human mucociliary epithelium can recapitulate the heterogeneity of infection among different donors and SARS-CoV-2 variants and can be used for moderate throughput screening. Compounds that target host factors showed variability among patients in response to SARS-CoV-2, while direct-acting antivirals were effective against SARS-CoV-2 despite the heterogeneity of patients tested.

  PublisherOA PDFDOI

• Drug screen reveals new potent host-targeted antivirals against Mpox virus

  Research Square · 2025-06-05

  preprintOpen access1st authorCorresponding
  PublisherOA PDFDOI

• Endolysosome-targeted nanoparticle delivery of antiviral therapy for coronavirus infections

  Life Science Alliance · 2025-02-03 · 2 citations

  articleOpen access

  SARS-CoV-2 can infect cells through endocytic uptake, a process that is targeted by inhibition of lysosomal proteases. However, clinically this approach to treat viral infections has afforded mixed results, with some studies detailing an oral regimen of hydroxychloroquine accompanied by significant off-target toxicities. We rationalized that an organelle-targeted approach will avoid toxicity while increasing the concentration of the drug at the target. Here, we describe a lysosome-targeted, mefloquine-loaded poly(glycerol monostearate-co-ε-caprolactone) nanoparticle (MFQ-NP) for pulmonary delivery via inhalation. Mefloquine is a more effective inhibitor of viral endocytosis than hydroxychloroquine in cellular models of COVID-19. MFQ-NPs are less toxic than molecular mefloquine, are 100-150 nm in diameter, and possess a negative surface charge, which facilitates uptake via endocytosis allowing inhibition of lysosomal proteases. MFQ-NPs inhibit coronavirus infection in mouse MHV-A59 and human OC43 coronavirus model systems and inhibit SARS-CoV-2 WA1 and its Omicron variant in a human lung epithelium model. Organelle-targeted delivery is an effective means to inhibit viral infection.

  PublisherOA PDFDOI

• SARS-CoV-2 nucleocapsid induces hyperinflammation and vascular leakage through the Toll-like receptor signaling axis in macrophages

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-28 · 1 citations

  preprintOpen access

  Tens of thousands of severe COVID-19 cases are hospitalized weekly in the U.S., often driven by an imbalance between antiviral responses and inflammatory signaling, leading to uncontrolled cytokine secretion. The SARS-CoV-2 nucleocapsid (N) protein is a known immune antagonist, but its role in macrophage-driven cytokine storms is unclear. We demonstrate that N functions in a pathway-specific manner, specifically amplifying nuclear factor κB-related transcripts upon Toll-like receptor 7/8 stimulation. Moreover, we show that this is a conserved feature of pathogenic coronaviruses, with the delta variant N being the most pro-inflammatory. Our interaction networks suggest the delta variant N drives inflammation through interactions with several stress granule-related proteins. Profiling of secreted cytokines revealed that supernatants from the delta variant N-expressing macrophages disrupt brain and heart endothelial barriers, implicating N in COVID-19-associated cognitive and cardiac complications. Our findings highlight N-mediated immune imbalance as a driver of severe COVID-19 and identify N as a promising therapeutic target to mitigate hyperinflammation.

  PublisherOA PDFDOI

• Phosphatidylserine receptors TIM-1 and AXL mediate tick-borne Powassan virus entry

  iScience · 2025-11-05 · 1 citations

  articleOpen accessSenior author

  studies in wild-type C57BL/6 mice. Among the receptors studied, phosphatidylserine (PtdSer)-recognizing TIM-1 and AXL receptors facilitated higher infection. To further validate our findings, a neutralization assay was performed in which the soluble form of the TIM-1 receptor efficiently blocked infection. In addition, we demonstrated that PtdSer receptor-expressing cells in cortical organoids and mouse brain tissues were infected with the virus. We conclude that PtsSer moieties on POWVs' surface facilitate viral entry through the cellular TIM-1 and AXL receptors.

  PublisherDOI

• Primary Human Distal and Proximal Airway Models for Higher-throughput Drug Screening of Anti-SARS-CoV-2 Compounds

  American Journal of Respiratory and Critical Care Medicine · 2025-05-01

  article

  Abstract Rationale: Human stem cell-based airway models are useful for studying the effects of environmental injuries like respiratory viruses and cigarette smoking on proximal and distal airway health because of their human relevance and greater translational impact. Two such models, air-liquid interface (ALI) cultures and alveolar type 2 (AT2) organoids, recapitulates he proximal and distal human airways respectively and have been critical tools in the field. However, converting them into a higher-throughput system either for drug screening or to study disease mechanisms remains a challenge due to their complexity. Here, we present primary human stem cell-based proximal and distal airway models of SARS-CoV-2 infection of multiple variants to i) perform a drug screen with the 96-transwell (TW) ALI model and ii) study the effect of cigarette smoke in drug-treated SARS-CoV-2 infection with the AT2 organoid model.Methods: We optimized 96-TW ALI cultures with primary human airway basal stem cells and 24-well TW Matrigel cultures with primary human AT2 organoids. For the drug screen, 2100 compounds were tested in the SARS-CoV-2 infected ALI cultures and subsequently examined for viral infectivity and drug effectiveness. To study smoke-induced DNA-damage mechanisms in the distal airway, we also treated AT2 organoids with cigarette smoke extract (CSE), then followed by treatment with a DNA damage response (DDR) inhibitor. Organoids were later infected with SARS-CoV-2 then analyzed for drug toxicity and viral infectivity.Results: The 96-TW ALI model shows efficacy in recapitulating the heterogeneity among different donors and in the degree of infection severity among different SARS-CoV-2 variants. While host-factor targeted compounds were not consistently effective, the direct-acting antivirals showed consistent results. Using this model, we characterized a new anti-viral therapy that is effective working against multiple variants. Cigarette smoke exposure (CSE) was correlated with a five-fold increase in viral replication in AT2 organoids and two-to-three-fold increase in infected cells within ALI. AT2 organoids treated with CSE also lose AT2 characteristics and begin to de-differentiate relative to non-treated organoids.Conclusions: The present work shows both the 96-well TW ALI and AT2 organoid plate formats are biologically relevant systems to study environmental effects and perform drug screens. Current work involves studying DDR inhibitor effects on AT2 organoids after exposure to CSE and infection with SARS-CoV-2. These higher-throughput systems have potential for use in drug screens for other respiratory viruses or to study environmental influences on human airways.

  PublisherDOI

• Open Source Repurposing Reveals Broad-Spectrum Antiviral Activity of Diphenylureas

  Viruses · 2025-03-07 · 2 citations

  articleOpen access

  The pandemic threat from newly emerging viral diseases constitutes a major unsolved issue for global health. Antiviral therapy can play an important role in treating and preventing the spread of unprecedented viral infections. A repository of compounds exhibiting broad-spectrum antiviral activity against a series of different viral families would be an invaluable asset to be prepared for future pandemic threats. Utilizing an open innovation crowd-sourcing paradigm, we were able to identify a compound class of diphenylureas that exhibits in vitro antiviral activity against multiple viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), adenovirus, dengue virus, herpes, and influenza viruses. Compound 4 among the series exhibits strong activity against dengue virus, a growing global health problem with high medical need and no approved antiviral drug. The compounds are active against SARS-CoV-2 in a primary human stem cell-based mucociliary airway epithelium model and also active in vivo, as shown in a murine SARS-CoV-2 infection model. These results demonstrate the potential of the chemical class as antivirals on the one hand and the power of open innovation, crowd-sourcing, and repurposing on the other hand.

  PublisherOA PDFDOI

Frequent coauthors

• Gustavo Garcia

  University of California, Los Angeles

  114 shared

• Arunachalam Ramaiah

  Milwaukee Health Department

  112 shared

• Brigitte N. Gomperts

  Samueli Institute

  81 shared

• Samuel W. French

  University of California, Los Angeles

  61 shared

• Deisy Contreras

  Cedars-Sinai Medical Center

  53 shared

• Robert Damoiseaux

  52 shared

• Kouki Morizono

  University of California, Los Angeles

  44 shared

• Ren Sun

  40 shared

Education

• Postdoc fellowship, Molecular and Medical Pharmacology

  University of California Los Angeles David Geffen School of Medicine

  2008

• PhD, Cell and Molecular Biology

  University of Arkansas Fayetteville

  2003

• MVSc, Pathology

  Indian Veterinary Research Institute

  2000

• BVSc (DVM)

  Madras Veterinary College

  1998