Does Lumpy Skin Disease Have the Potential to Become Zoonotic?

Abstract

The purpose of this letter is to call the attention of the scientific community to the recent manuscript published by Tomar and Khairnar [1]. In this study, using a metagenomic analysis, the authors discovered the presence of genome fragments of Capripoxvirus lumpyskinpox (LSDV) in nasopharyngeal swab samples (obtained from SARS-CoV-2 surveillance activities during 2023) collected from 12 human subjects located in the districts of Nagpur, Chandrapur, and Bhandara state of Maharashtra, India. Herein, we present our perspective about the potential of LSDV to infect humans as well as our suggestions about further steps to confirm the results published by Tomar and Khairnar.

LSDV belongs to the poxvirus family and capripoxvirus genus. It produces lumpy skin disease—a highly contagious cattle-buffalo vector-borne disease reportable to the World Organization for Animal Health (WOAH) [2]. Currently, none of the viral species included in this genus are considered zoonotic agents. The poxvirus family contains multiple viral species which can infect a variety of hosts (Figure 1). Currently, a total of eleven poxviruses linked to four poxviridae genera have demonstrated the ability to infect humans (Figure 1).

Although multiple poxviruses have the capability to infect humans, the most relevant poxviruses for public health are grouped in the orthopoxvirus genus (Figure 1A). These include orthopoxvirus variola (one of the deadliest viruses in human history) [3] and orthopoxvirus monkeypox (the most relevant orthopoxvirus infection in humans in the orthopoxvirus variola post-eradication era) [4]. These two viruses, along with the molluscum contagiosum [5], are the only poxviruses with the ability to promote sustained human-to-human transmission. This ability is an important condition for a zoonotic virus that has crossed the species barrier, like orthopoxvirus monkeypox, to become significant for public health.

When considering the phylogenetic relationship of capripoxviruses with other poxviruses that have the ability to infect humans, capripoxviruses are most closely related to viruses in the genus Yatapoxvirus (Figure 1), which includes yatapoxvirus tanapox and yatapoxvirus yabapox. Neither of these viruses are regarded as a major human health threat [6]; however, capripoxviruses and yatapoxviruses are linked to vector transmission [7]. This characteristic, along with the capability of poxviruses to replicate in the cytoplasm, are two conditions positively associated with the potential zoonotic risk of a viral agent [8].

Another important aspect of LSDV to consider is its potential to produce cross-species spillover. Between 2021 and 2023, six new animal species were discovered to be clinically infected with this virus [9] (Figure 1A). Interestingly, half of these new hosts were detected in India during 2022–2023 [9], a finding that correlates with the sampling year of the study conducted by Tomar and Khairnar. It is important to consider that all animal species susceptible to infection with LSDV are related to the Artiodactyla taxonomic order, which demonstrates the strong affinity of LSDV to infect hoofed mammals (Figure 1A). In vitro LSDV has shown its ability to replicate in a limited number of cells from human origin, including human lung adenocarcinoma (A549) and noncancerous cells such as human foreskin fibroblasts (HFF) (very limited replication) [10]. However, in both cases, replication was significantly lower than in cells from bovine origin (Madin–Darby bovine kidney), showing the low susceptibility of LSDV to infect cells from human origin [10]. The specific receptors used for LSDV to infect A549 and HFF cells are unknown.

Infections of humans with zoonotic poxviruses produced by interaction with hoofed mammals are typically described as zoonotic occupational diseases, which result in mild clinical infections characterized by the presence of cutaneous lesions. Based on this trend, zoonotic occupational disease might be an expected scenario for LSDV in the event its ability to infect humans is established. Yet, in the study published by Tomar and Khairnar, patients with LSDV-positive samples were apparently clinically asymptomatic. Also, as mentioned by the authors, the fact that positive samples came from the upper respiratory tract is intriguing, suggesting that the potential transmission in these patients occurred intranasally by aerosols. It contrasts with the mode of infection of zoonotic poxviruses transmitted by hoofed mammals, where the main source of infection in humans is contact with skin lesions of infected cattle.

Interestingly, experimental intranasal inoculation of white mice with LSDV resulted in the absence of clinical signs and lesions in internal organs (Figure 1B) [11]. However, it was possible to detect a fragment of the LSDV intermittently from blood samples until 21 days post infection (dpi) (Figure 1B). The ability of LSDV to infect white mice intranasally in absence of clinical signs, was posteriorly confirmed by the development of neutralizing antibodies at 14 dpi (Figure 1B), showing the ability of LSDV to infect animal species beyond the Artiodactyla taxonomic order. In this sense, the subclinical phenotype displayed by LSDV, not only in white mice inoculated intranasally, but also in other laboratory animals intradermally inoculated (Figure 1B), represents an important piece of evidence about the possible clinical scenarios that may be observed during the infection of LSDV in species not within the Artiodactyla taxonomic order. It signifies a possible explanation for the results published by Tomar and Khairnar, where the detection of genome fragments of LSDV was produced from asymptomatic patients.

Overall, interactions between multiple ecological factors, including pathogen pressure (shedding rate, dissemination, and survival), human exposure to the pathogen and host susceptibility must be taken into account to determine the probability of a zoonotic spillover event [12]. In the case of LSDV, the pathogen pressure involves a complex natural infectious cycle [13, 14], which can lead to sustained dissemination of this agent and potentially promote zoonotic spillover (Figure 2A). Notably, this zoonotic spillover may also be promoted using live attenuated vaccines [14] (Figure 2A). Since the first detection of LSDV in Zambia in 1929 [2], outbreaks of LSDV in cattle have been reported in at least 58 countries in Africa and Asia [2, 13, 14] (Figure 2B). Specifically, in India, where Tomar and Khairnar's study was conducted, several outbreaks of LSDV were reported between 2019 and 2023, affecting about 3.3 million cattle [11]. In Maharashtra, clinical cases were reported in 2020, 2022, and 2023. During 2023, Maharashtra had the second most active LSDV cases amongst Indian states (Figure 2C) [13], potentially increasing the probability of exposure to humans in that region and supporting the results presented by Tomar and Khairnar. Overall, LSDV has diverged into at least seven phylogenetic clades (Figure 2D). LSDV lineages detected in India have been associated with clade 1.2 and sub clades 1.2.1 and 1.2.2 (Figure 2D). Interestingly, when we conducted a phylogenetic analysis using the DNA polymerase sequences of the LSDV strains most genetically related to the viral genome reads reported by Tomar and Khairnar in 2024, we found that the strains were linked to the two phylogenetic subclades comprising the previously reported Indian LSDV strains (Figure 2D). This supports the hypothesis that the possible infections in humans might have happened with viral strains from diverse genetic origins. However, considering the limited evidence presented by Tomar and Khairnar, it is not possible to determine whether the results are due to an active infection or merely environmental or nonspecific detection. In this sense, it is important to consider that exposure of humans to foot and mouth disease virus (FMDV), an agent that affects hoofed animals, resulted in the detection of the virus in nasal swabs in absence of clinical signs and the development of antibodies against FMDV [15]. It represents another plausible explanation for the results published by Tomar and Khairnar, supporting the idea of mere environmental detection.

In conclusion, the susceptibility of humans to infection with LSDV remains the most important unanswered question. Based on the current evidence, it is premature to suggest that LSDV has significant zoonotic potential. At this point and considering evidence from FMDV, environmental nonspecific detection could be the most plausible explanation for the results published by Tomar and Khairnar. The initial detection of LSDV genetic material in humans (an unexpected host) by metagenomics can be considered noteworthy, but doesn't necessarily prove causation of disease. Instead, as discussed by Tomar and Khairnar, this discovery is merely the first step in the process to ascertain the ability of LSDV to produce infection in humans, a postulate that must be confirmed by further investigations. Based on the in vitro information assessing the ability of LSDV to infect human cells, we could suggest that the susceptibility of humans to LSDV might be considered low. However, considering the ability of LSDV to produce subclinical infections in laboratory animals, at this point, we cannot rule out the possibility of subclinical outcomes produced by LSDV in humans. It was unfortunate that no additional tests (viral isolations, serological tests) were conducted during this study to confirm the results obtained by metagenomics. The detection of antibodies against LSDV in these patients would have given indirect evidence of the ability of this pathogen to infect humans. Considering all the above, we suggest a serological survey be conducted in humans within LSDV-prevalent zones to gain more insights into the results published by Tomar and Khairnar.

The authors declare no conflicts of interest.