Lumpy Skin Disease Virus Suppresses Key Immune Genes in Cattle, Study Finds

Lumpy skin disease, once largely confined to the African continent, has become one of the most consequential transboundary viral threats to cattle worldwide, and a new field study from India offers one of the most detailed pictures yet of how the virus rewires the immune systems of naturally infected animals. Researchers working during outbreaks in Puducherry and adjacent districts of Tamil Nadu examined 21 clinically affected cattle alongside six healthy controls, combining clinical staging, hematology, molecular diagnostics, histopathology, immunohistochemistry, serology, and quantitative analysis of cytokine gene expression. Their findings, published in Frontiers in Virology, point to a coordinated suppression of both proinflammatory and anti-inflammatory signaling pathways that may explain why the lumpy skin disease virus persists so effectively in affected herds.

The causative agent, lumpy skin disease virus, is a member of the genus Capripoxvirus within the family Poxviridae. Infection produces fever, nasal and lacrimal discharge, lymph node enlargement, and the characteristic firm skin nodules that progress to necrotic, ulcerated lesions. Beyond the visible toll on the animals, the disease carries severe economic consequences: reduced milk yield, weight loss, infertility, abortion, hide damage, movement restrictions, and mortality. The recent epidemic in India resulted in more than 155,000 cattle deaths and an estimated economic loss of roughly 2.2 billion US dollars, underscoring the urgency of understanding the host-pathogen interaction at a mechanistic level.

The study team, drawn from the ICAR-National Institute of Veterinary Epidemiology and Disease Informatics in Bengaluru and the Rajiv Gandhi Institute of Veterinary Education and Research in Puducherry, classified the affected animals into early, mid, and late stages of disease based on the duration of clinical signs. Most of the affected cattle were crossbred Jersey animals, and females accounted for 90.5 percent of cases, with a higher proportion of cases observed in calves under one year of age. This demographic pattern is consistent with earlier reports suggesting that young and crossbred animals experience greater disease severity, possibly reflecting differences in immune maturity and genetic background.

Clinical observations tracked the expected progression of infection. Early-stage animals presented with mild fever, ocular and nasal discharge, brisket and limb edema, and localized nodules over the neck, abdomen, and perineum. Mid-stage cattle developed higher rectal temperatures, persistent discharge, respiratory distress, and more widespread nodularity. In the late stage, nodules underwent necrosis and rupture, producing sit-fast lesions, scabs, and ulcerated wounds prone to secondary bacterial infection. These stage-dependent findings align with the classical descriptions of the disease established decades ago and confirm the multisystemic nature of capripoxvirus infection in cattle.

Hematological analysis revealed a profile of active systemic inflammation. Total leukocyte counts rose significantly with disease progression, peaking in late-stage animals at 13.17 thousand cells per cubic millimeter compared with 4.87 in healthy controls. Absolute lymphocyte counts followed the same trajectory, reaching their highest values in late-stage cases, and absolute monocyte counts increased progressively with disease severity. Eosinophil and basophil counts were also significantly elevated. Meanwhile, mean corpuscular volume and mean corpuscular hemoglobin declined significantly in affected animals, changes the authors interpret as reflecting altered erythrocyte dynamics during chronic inflammation. Together, the blood picture of leukocytosis, lymphocytosis, monocytosis, and eosinophilia documents a sustained immune activation even as other arms of the immune response falter.

Molecular detection using conventional PCR targeting the partial P32 gene, a Capripoxvirus-specific marker, identified viral DNA in 52.4 percent of nasal swabs and 57.1 percent of skin biopsy samples. Detection rates in nasal swabs were highest during the early stage and declined as disease progressed, consistent with active viral replication and shedding in respiratory secretions during the acute phase. Skin biopsies, by contrast, remained positive across all stages, supporting their status as the most reliable diagnostic specimen throughout the course of infection. Serological testing by indirect ELISA using a recombinant LSDV antigen detected antibodies in only four of the 21 affected animals, an overall seropositivity of 19 percent, a figure the researchers attribute to delayed seroconversion and variability in humoral responses under natural field conditions.

Histopathological examination of skin tissues revealed changes concentrated in the dermis and deep dermis. The epidermis showed little beyond hyperplasia of the epithelial layer, but the underlying dermis exhibited necrosis and severe infiltration of histiocytic cells, particularly around perivascular spaces and between muscular bundles. These findings, indicative of vasculitis and myositis, mirror the classic pathological descriptions of the disease and highlight how vascular inflammation drives the edema, tissue damage, and nodule formation characteristic of infection. Immunohistochemistry, performed on a subset of samples, detected viral antigen as granular golden-brown deposits in ten of twelve tissues examined, with the strongest localization in the basal layer of the epidermis, the epithelial matrix lining hair follicles, and the epithelial cells of sweat and sebaceous glands. This tropism for proliferative keratinocytes and metabolically active follicular epithelium likely explains both the nodular lesions and the potential for viral shedding through glandular secretions.

The most striking result emerged from the cytokine expression analysis. Using quantitative real-time PCR on peripheral blood mononuclear cells and skin tissues, normalized to the housekeeping gene GAPDH, the team measured the relative expression of five cytokine genes representing both arms of the adaptive immune response. The Th1-associated genes IL-2, IFN-gamma, and GM-CSF, and the Th2-associated genes IL-4 and IL-10, were all markedly downregulated in infected animals compared with healthy controls, in both blood-derived and skin-derived samples. In late-stage animals, expression of several of these genes fell to near-undetectable levels, while healthy cattle maintained robust expression, particularly of IFN-gamma in skin tissue.

This broad suppression carries significant mechanistic implications. IL-2 is central to the expansion of antigen-specific T cells, and its reduction signals impaired cell-mediated antiviral immunity. IFN-gamma, a critical coordinator of antiviral defense and macrophage activation, was among the most profoundly suppressed genes, a change that would be expected to facilitate viral persistence within host tissues. GM-CSF supports the activation and differentiation of innate immune cells, and its loss compromises the recruitment and function of the very cells needed to clear infection. Even IL-10, typically regarded as an anti-inflammatory regulator, was downregulated, suggesting that the virus disrupts immune homeostasis in a way that permits prolonged inflammation without effective pathogen clearance. The authors interpret this coordinated dampening as a deliberate viral strategy of immune evasion, one that prolongs viral persistence, sustains inflammatory pathology, and increases susceptibility to secondary infections.

The study’s cross-sectional design, in which animals at different clinical stages were sampled rather than the same individuals followed longitudinally, represents a limitation acknowledged by the authors, since repeated sampling of field cases was not feasible. Nevertheless, by integrating clinical, hematological, molecular, pathological, immunological, and transcriptional data from naturally infected cattle, the work provides a unusually comprehensive view of lumpy skin disease pathogenesis under real outbreak conditions. The identification of cytokine modulation as a key mechanism of immune evasion opens potential avenues for biomarker development, distinguishing susceptible from resilient animals, and informing immunomodulatory approaches to complement existing vaccination strategies. As the virus continues to expand its geographic range across Asia and the Middle East, understanding how it disarms the bovine immune system may prove essential to controlling one of the most economically devastating diseases of livestock.

Subject of Research: Immune dysregulation and cytokine suppression in cattle naturally infected with lumpy skin disease virus

Article Title: Immuno-pathological studies of lumpy skin disease outbreaks in cattle

Article References: Vigneshwar, G., Avinash, L. W., Javed, A. A., Sunil, T., Abhinaya, M., Mukhopadhyay, H. K., Rajalakshmi, K., Poobitha, S., Uma, S., Kumar, R., Gopalakrishnan, N. M., Sharddha, B., Chandana, U. R., & Manjunatha Reddy, G. B. (2026). Immuno-pathological studies of lumpy skin disease outbreaks in cattle. Frontiers in Virology, 6, Article 1907549. https://doi.org/10.3389/fviro.2026.1907549

Image Credits: AI Generated

DOI: 10.3389/fviro.2026.1907549

Keywords: lumpy skin disease, LSDV, cattle, capripoxvirus, cytokines, immune evasion, immunohistochemistry, PCR, hematology, histopathology, India, veterinary virology