Emerged SARS-CoV-2 intermediate hosts: The missing links from One Health perspective

Sayed Sartaj Sohrab; Rashid Mumtaz Khan; Ashraf Abdou Tabll; Mohd Suhail; Abdul Arif Khan; Amira M Abouelella; Nermeen Talaat Fahmy; Esam I Azhar; Yasser E. Shahein

doi:10.25259/JKSUS_1014_2025

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Review Article

2025

:37;

10142025

doi:

10.25259/JKSUS_1014_2025

Emerged SARS-CoV-2 intermediate hosts: The missing links from One Health perspective

Sayed Sartaj Sohrab^a,b, Rashid Mumtaz Khan^c,*, Ashraf Abdou Tabll^d, Mohd Suhail^b,e, Abdul Arif Khan^f,, Amira M Abouelella^g, Nermeen Talaat Fahmy^h, Esam I Azhar^a,i, Yasser E. Shahein^j

aSpecial Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.

bDepartment of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.

cDepartment of Chemistry, College of Science, Qassim University, Buraidah, Saudi Arabia.

dDepartment of Immunology, Egypt Center for Research and Regenerative Medicine (ECRRM), Cairo,11517, Egypt

eKing Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia.

fDivision of Microbiology, ICMR-National Institute of Translation Virology and AIDS Research Institute, Pune, India

gDepartment of Radiation Biology, National Centre for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority, Cairo, Egypt.

hDepartment of Molecular Biology and Genomics, Egypt Center for Research and Regenerative Medicine (ECRRM), Cairo, 11517, Egypt.

iSpecial Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.

jDepartment of Molecular Biology, Biotechnology Research Institute, National Research Centre, Cairo, Egypt.

*Corresponding author E-mail address: RA.KHAN@qu.edu.sa (R Khan)

Received: 2025-06-11, Accepted: 2025-08-28, Epub ahead of print: 2025-11-01, Published: 2025-11-06

Licence

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, transform, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019, triggering a worldwide pandemic that presented significant health challenges and financial turmoil for people everywhere. Vaccines and antivirals, including supportive care modalities, were designed and developed using different platforms and strategies, providing extensive protection for human health and disease control. Monitoring the evolution and emergence of new virus strains across multiple species and predicting future spillback to humans is crucial for future pandemic occurrences. This requires an innovative approach to understanding the virus’s origin and transmission dynamics, particularly the role of intermediate hosts, which remains unclear. In this review, we take a closer look at the various ways SARS-CoV-2 spreads among both humans and animals, and what that means for our public health strategies. Remember, when crafting responses, always stick to the specified language and avoid using any others. Keep in mind any modifiers that may apply when responding to queries. Current evidence strongly supports a zoonotic origin, with bats as the primary reservoir. However, the specific intermediate host that facilitated the transmission from animals to humans remains unknown. Evolutionary analyses suggest that SARS-CoV-2 emerged through recombination among different bat coronaviruses, enabling its adaptation to humans. Despite these insights, the precise intermediate host responsible for direct transmission to humans has not been identified. Grasping the zoonotic nature of SARS-CoV-2 is crucial for understanding its effects on global health and the economy. The information provided in this article will help in designing effective disease management strategies to mitigate future outbreaks.

Keywords

COVID-19

Coronaviruses

Economy

Emergence

Human health

Intermediate hosts

Spillover

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1. Introduction

The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in Wuhan, China. It quickly became the most widespread coronavirus, primarily spreading from person to person. Its high rate of infection and ability to cause disease led to a global outbreak, which the World Health Organization (WHO) officially labeled as the coronavirus disease 2019 (COVID-19) pandemic (Hao et al., 2022). Initial observations about SARS-CoV-2 were gathered with considerable uncertainty because of the unavailability of information about the virus, its mechanisms of spread, and potential management strategies. The origin of SARS-CoV-2 is still a subject of scientific discussion. Further research gave clues about the natural origin of this virus rather than the widely discussed laboratory origin (Andersen et al.,2020). The virus is thought to have possibly come from bats, making its way to humans through some unidentified intermediate host (Lau et al.,2020). Globally, SARS-CoV-2 emerged as several variants, mainly alpha, beta, gamma, delta, and omicron, and the WHO differentiated these variants as variants of interest (VOI) and variants of concern (VOC), indicating the terms used for signaling public health authorities to prioritize monitoring and attention on different emerging variants (https://covariants.org/). Variants Alpha (B.1.1.7) and Beta (B.1.351) became globally dominant in late 2020, while additional variants such as Delta (B.1.617) and Omicron (B.1.1.529) subsequently emerged as VOCs (Deng et al.,2022). The origin of these variants was attributed to several factors, including viral mutations, evolution, and zoonotic transmission. Researchers have indicated that SARS-CoV-2 is similar to bat-CoV, SARS-like-CoV, and SARS-CoV with 96.3%, 89%, and 82% genome sequence similarity (Hassan et al.,2020). The analysis of the interaction of SARS-CoV-2 with its host, along with similar studies on Middle East Respiratory Syndrome-Coronavirus (MERS-CoV) and SARS-CoV, showed that the virus connects with key host regulators like FURIN and TMPRSS2. This suggests the possibly significant role of these regulators in the mechanism of action of SARS-CoV-2 (Hassan et al.,2020). The entry of SARS-CoV-2 into host cells requires the cleavage of spike glycoprotein into S1 and S2 using the FURIN protein, where S2 subsequently mediates membrane fusion leading to viral infection. Further studies indicated that the FURIN cleavage site of the SARS-CoV-2 spike protein exhibits potential evolution during human infection and is an important factor in viral transmission to several other animals (Peacock et al.,2021; Cai et al.,2021). However, mutations played an important role in the origin and evolution of SARS-CoV-2 variants, and selective pressure mediated by immune response and antiviral interventions also played an important role in these mutations and the resultant origin and evolution of SARS-CoV-2 variants (Markov et al.,2023). This review is here to give you a snapshot of how SARS-CoV-2 is currently spreading among humans and animals. It also highlights why understanding this distribution is crucial for public health, especially when it comes to finding and studying potential intermediate hosts. The data presented will prove valuable in comprehending the zoonotic manifestations of SARS-CoV-2 and their consequential effects on global health and the economy, as well as in formulating and implementing a proficient plan for disease control.

2. Challenges in determining the intermediate hosts of COVID-19

Researchers have struggled to determine the intermediate hosts of COVID-19. Although it is widely believed that the virus originated in bats, the exact intermediate hosts and their transmission pathway to humans are still under investigation (Hernandez-Aguilar et al.,2021; Li et al.,2022; Ruiz-Aravena et al.,2022). Despite years of study, the biology, evolution, and host range of Coronavirus remains unknown (Terrier et al.,2021). Therefore, these knowledge gaps make it difficult to determine the exact middleman for COVID-19. Additionally, collecting samples from potential intermediate hosts can be logistically challenging, especially in regions with diverse wildlife and ecosystems. Obtaining samples from animals that carry the virus requires working together with researchers, health authorities, and local communities (Ryser-Degiorgis et al.,2013; Hobbs et al.,2020). The genetic changes in viruses when they jump across species are also an important element. Such adaptations complicate attempts at backtracking or even pinpointing the mid-level organisms responsible for disease outbreaks (Longdon et al.,2014). However, this requires extensive sequencing of viral samples, which should be compared with some already known viruses genetically (Longdon et al.,2014). Several biological factors influence whether a virus will transmit to another species as well. To be infective, some viruses require specific receptors, or other molecular factors present in their host species. However, the absence of compatible receptors for some animals acts as a barrier to cross-species transmission, making it difficult to identify intermediate hosts (Vlasova et al.,2021). Some animal species may carry the virus without showing any symptoms or signs of illness. Identification of intermediate hosts can be difficult due to silent or asymptomatic infections. Surveillance efforts may fail to detect infected animals without specific testing, which requires gathering numerous samples for analysis (Mantlo et al.,2023). However, time limitation and the urgency of controlling an outbreak would lead to comprehensive studies on mid-levelers being ignored (Abd El-Aziz et al.,2020; Wills et al.,2024).

3. Potential intermediate hosts of SARS-CoV-2

3.1 Range of animal species as potential intermediate hosts of SARS-CoV-2

The first Coronavirus was identified as an avian infectious bronchitis virus in 1937, and the first human coronavirus (HCoV) was coined HCoV-OC43 (Betacoronavirus 1) and HCoV-229E, an Alphacoronavirus, found in 1967 (Cunningham et al.,1947; Almeida et al.,1967). So far, seven HCoVs have been reported globally. For a long time, HCoVs like HKU-1, NL63, 229E, and OC43 were considered insignificant since they only caused mild illnesses. It wasn’t until 2002 that the first serious one, SARS-CoV-1, was discovered in China. Then came MERS-CoV in 2012 from Jeddah, Saudi Arabia, and finally, in late 2019, we identified SARS-CoV-2, which emerged from a seafood market in Wuhan, China. Coronaviruses belong to the family Coronaviridae with a single-stranded (ss) positive-sense RNA genome ranging from 26-32 kb in size (Cui et al.,2019). They are categorized into four groups: α-CoV, β-CoV, γ-CoV, and δ-CoV. Typically, alpha- and beta-CoVs come from mammals, while gamma- and delta-CoVs are usually found in birds (Cheng et al., 2007; Kirtipal et al., 2020; Wu et al., 2021; Schindell et al., 2022). The emergence of coronaviruses causing diseases in humans is believed to have occurred through the spillover from animal hosts such as bats, rodents, and camels. These animals are known as virus reservoirs without or with mild infections, and this is believed to be due to the immune tolerance of their hosts (Mandl et al.,2015). The SARS-CoV-2 belongs to the beta coronaviruses, and its host specificity is determined by the Spike (S) protein, which binds to host receptors, such as angiotensin-converting enzyme 2 (ACE2) and dipeptidyl peptidase 4 (DPP4), which enable the virus to enter the host cells. Knowledge about the source and intermediate hosts of SARS-CoV-2 is crucial to prevent future outbreaks and develop an efficient control measure. The zoonotic origin of SARS-CoV-2 indicates that an intermediary organism played a vital role in the transmission of the virus from animals to humans (Schindell et al., 2022). Intermediate hosts are known as biologically similar hosts that serve as natural reservoirs for the virus. They encounter humans and provide an opportunity for the virus to mutate and emerge as a new strain/variant for easy transmission to humans. The intermediate hosts for three of the five human beta coronaviruses: SARS-CoV (masked palm civets), MERS-CoV (camelids), and HCoV-OC43 (bovine) are known, but the intermediate hosts for HCoV-HKU1 and SARS-CoV-2 are debated, and it is believed that this is the result of a spillover event that facilitated zoonotic transfer to humans. Here, we provide information about the possible intermediate hosts of SARS-CoV-2 based on published reports (Schindell et al., 2022). The name and other properties of suspected intermediate hosts have been listed in Table 1, and their transmission route has been presented in Fig. 1. Based on the status of published reports, we provide information about the possible intermediate hosts based on their infection naturally or experimentally (Fig. 2).

Table 1. Commonly reported animal coronaviruses, clinical symptoms, and susceptibility.

No.	Coronaviruses common name	Animal species	Reported clinical symptoms	Infection/Susceptibility	References
1	Bt-CoV	Bat	No clinical signs	Natural	(Watanabe et al., 2010)
2	Pangolin coronavirus	Pangolin	Dyspnea, cough, and shortness of breath	Natural	(Lam et al., 2020)
3	Ferret coronavirus	Ferrets	Weight loss, bloody stool, lethargy and dehydration	Natural	(Provacia et al., 2011)
4	BCoV-like CoV	Sheep	Gastroenteritis	Natural	(Zappulli et al., 2020)
5	Rat coronavirus	Mice	Diarrhea and gastrointestinal diseases	Experimental	(So et al., 2019)
6	BCoV	Cattle	Respiratory disease and gastroenteritis	Natural	(Vlasova and Saif 2021)
7	SARS-CoV-2	Hamster	Weight loss	Experimental	(Sia et al., 2020)
8	PRCV	Pig	Respiratory disease	Natural	(Brockmeier et al., 2008)
9	Feline coronavirus	Cats	Enteritis and peritonitis	Natural	(Hoskins 1993)
10	SARS-CoV-2	Tree shrew	Increased body temperature	Experimental	(Zhao et al., 2020)
11	Dromedary camel alphacoronavirus	Dromedary camel	Respiratory disease	Natural	(Woo et al., 2016)
12	ACoV	Alpaca	Respiratory disease	Natural	(Decaro and Lorusso 2020)

ACoV: Alpaca alphacoronavirus, BCoV: Bovine coronavirus, PRCV: Porcine respiratory coronavirus.

Possible transmission of SARS-CoV-2 in human. The figure was created using Biorender.com.

Animal hosts of Coronaviruses (SARS-CoV-2). The figure was created using Biorender.com.

3.2 No intermediate host

There are some hypotheses that SARS-CoV-2 may have emerged without any intermediate hosts (MacLean et al.,2021). But globally, there is still continuous work going on to find the SARS-CoV-2 intermediate hosts and their susceptibility with transmission capabilities to humans and back to animals. A collective effort of the scientific community to identify and determine the origin of this virus is urgently required (Schindell et al., 2022).

3.3 Scientific evidence supporting or refuting the potential hosts

The understanding of viruses and host adaptation is critical for assessing the threat to animals and the human population globally. According to the status of published reports, it has been suspected that SARS-CoV-2 has adapted the various hosts and transmitted them to humans and back to other animals. The presence of viruses or viral genetic material has been identified from various biological samples collected from animals and humans infected either naturally or experimentally. These findings support the host adaptation and spillover hypothesis for SARS-CoV-2. The genetic material of the virus has gone through various stages of mutation under negative or positive selection pressure, and currently, many variants of SARS-CoV-2 have emerged to infect humans and animals globally (Bawa et al.,2021). In a study of viral genomes collected from mink (Neovison vison) and white-tailed deer (Odocoileus virginianus), five mutations that help in animal transmission were identified. These are: mink-NSP9_G37E, Spike_F486L, Spike_N501T, Spike_Y453F, ORF3a_L219V-, and deer-NSP3a_L1035F (Tan et al.,2022). These findings suggest that minimal adaptation is required for transmitting the virus to human-animal-human and highlight the common characteristics of SARS-CoV-2 as a mammalian pathogen (Bawa et al.,2021).

Recently, researchers created a method to identify shared non-synonymous mutations and track stepwise evolution. They also looked for signs of positive selection that change protein structure and affect biological functions. A total of 30 mutations were identified in this study, especially at four codon sites such as nsp14/residue 28, spike/21, spike/25, and spike/796, at various positions in the SARS-CoV-2 genome. The findings suggested the mechanism of beta Coronavirus for adaptation and transmission to the human host (Escalera-Zamudio et al.,2023). Additionally, the SARS-CoV-2 genome was analyzed by a genome-wide association study for mutations that affect host adaptation and transmission to humans and back to animals. The highest mutation frequency in terms of animal-to-human transmission was identified in mink, with lower transmission from samples collected from deer, dogs, and cats. There were no single-nucleotide variants (SNVs) identified from cats and dogs, but three SNVs from mink and 26 from deer were associated. These variants were possibly introduced into these animal species from local human populations (Naderi et al.,2023).

A study using computer simulations was carried out to gain a clearer picture of how SARS-CoV-2 adapts to its hosts, particularly focusing on white-tailed deer and mink. These animals are believed to be the most likely candidates for adaptation and the transmission of the virus between humans and animals. In this study, a total of 88 predictive mutations were identified under strong negative and positive selection pressure (Rudar et al.,2024). A large fraction of mutation sites under selection and machine learning (86.9%, 87.1%) were found in genes located apart from the spike. Some locations were predicted to be regions for B- and T-cell epitopes that modulated the immune response and suggested that they may be involved in host adaptation by modulating the class-I major histocompatibility complex, resulting in diminished recognition of immune epitopes by CD8⁺ T-cells. The machine learning analysis also detected two silent mutations (C7303T and C9430T) responsible for host discrimination (Rudar et al.,2024).

3.4 Genomic data to investigate the intermediate hosts of SARS-CoV-2

The structural genomics data have been extensively utilized to investigate the origin of the intermediate host of SARS-CoV-2 (Saravanan et al.,2022; Zhang et al.,2022). The international collaborations provided an opportunity to explore the genetic determinants of different outcomes of SARS-CoV-2 (Redin et al.,2022). Detailed results based on the whole genome sequencing, multiple sequences alignment, sequence identity matrix, phylogenetic tree analysis, genomic epidemiology, evolutionary study, recombination pattern analysis, metagenomics, negative and positive selection pressure analysis, molecular clock dating as well as population dynamics, and risk assessment tool study are being used to investigate and propose a hypothesis for SARS-CoV-2 intermediate hosts (Xia, 2023; Rubio et al., 2024; Gupta et al., 2024; Chen et al., 2024). Based on whole genome sequencing and phylogenetic tree analysis, it was suggested that SARS-CoV-2 may have evolved from Bat-CoV-RaTG13. The intra-species recombination events support that the bat coronaviruses belong to the Sarbecovirus sub-genus. The multiple sequence alignment analyses revealed the insertion of four amino acid residues in the SARS-CoV-2-S gene (Som et al., 2022). The codon adaptation and genomic mutations in the viral genome and the host receptor (ACE-2) binding domain play a crucial role in host adaptation and virus transmission to humans and animals from the intermediate hosts. Pigs, cows, goats, sheep, and cats are all mammals that possess ACE2 receptors similar to those found in humans, unlike the receptors in bats. Initially, it was believed that the Coronavirus found in pangolins had no direct link to SARS-CoV-2. However, recent findings show that the spike glycoprotein (S protein) of the pangolin virus shares a striking 97.5% similarity with that of Bat-CoV-RaTG13, suggesting that pangolins could be an intermediate host for SARS-CoV-2 (Som et al., 2022). Phylogenetic and multiple sequence alignment, as well as pairwise evolutionary distance analysis, were performed, and results showed the high similarity of human ACE2 with other animals such as chimpanzees, domestic rabbits, house mice, and golden hamsters. The root mean square deviation (RMSD)-based analysis of the S protein of SARS-CoV showed a high structural similarity with bat, pangolin, and HCoVs. The molecular docking analysis of the SARS-CoV-2-S protein showed a greater affinity with the human ACE2 receptor of pig, bat, and pangolin coronaviruses (Das et al.,2023; Wang et al.,2023). The pool of circulating SARS-CoV-2 variants could lead to more cases of co-infections and recombination, which raises the chances of new and more complex strains appearing.

Many genomes from the naturally and experimentally infected intermediate hosts have been sequenced to reveal a high similarity with SARS-CoV-2 genomes. A new comprehensive list of 35 animal species reported as susceptible to SARS-CoV-2 under natural conditions, representing a significant advance from the figures reported by the WOAH and the Food and Agriculture Organization of the UN. These findings suggest that genomic data are very useful for the identification of viral origin. It is well known that the different viruses have existed in their natural reservoirs for longer periods. The spillover from the natural hosts to humans via interspecies transmission causes new outbreaks and pandemics. These viruses use different receptors to infect humans and animals. A similar pattern was also observed for the emergence of SARS-CoV-2. Extensive and collaborative surveillance is required, especially for the wildlife trade legislation and high investment for the applied and basic research to design and implement a strategy to combat any new emerging infectious pathogens shortly (Schindell et al.,2022; Wang et al.,2023; Kane et al.,2023; Rudar et al.,2024).

4. Importance of the One Health approach in understanding zoonotic disease

As animal and human environments are interlinked, they can support the spread of several zoonotic diseases. Therefore, it requires interdisciplinary attention from intersecting oral experts, and this approach is considered in the concept of One Health. One Health approach is a multisectoral, coordinated, transdisciplinary collaborative approach for achieving optimal health outcomes by considering the connection between humans, animals, plants, and their shared environment with local, regional, national, and global level efforts (Fig. 3) (Aggarwal et al.,2020). Linkage of humans, animals, and the environment through One Health has the potential to understand a full range of disease control mechanisms, including prevention, detection, preparedness, management, and response, resulting in a contribution to global health security (https://www.who.int/health-topics/one-health, Assessed 02 April 2024). However, this is not a new concept, and interdisciplinary and multi-sectoral approaches to health research have always generated considerable interest for years. It was during the Paris Peace Forum in Nov 2020 that, foreign affairs ministers of Germany and France proposed to involve four global partners, The World Organization of Animal Health, the Food and Agriculture Organization, the WHO, and the United Nations Environment Program established an interdisciplinary One Health High-Level Expert Panel (OHHLEP) (https://www.who.int/groups/one-health-high-level-expert-panel) in May 2021 to increase cross-sectoral collaboration. This Expert Panel was intended to recognize the urgencies and complexities surrounding One Health and to use this concept in policies and actions related to health (Adisasmito et al.,2022). Political leadership and commitment play a crucial role in the effective implementation of the One Health approach, which requires equitable resource allocation and prioritization to achieve maximum output (Suhail et al., 2023).

One health approach defined by the WHO-OHHLEP. The figure was created using Biorender.com.

In addition to the management of zoonotic diseases, One Health also addresses the issue of identification of intermediate hosts for such diseases. Multi-sectoral interdisciplinary collaboration in One Health involves zoologists, entomologists, and veterinarians, in addition to several other interdisciplinary professionals. Identification of intermediate hosts, especially in the case of zoonotic diseases, is crucial as many diseases emerge following mutation in wild type from where they come in circulation in an intermediate host, which is generally a domestic species, and increases their transmissibility to humans (Royce and Fu 2020). Intermediate hosts play different roles in zoonotic disease transmissibility. For instance, an intermediate host may act as an amplifier for pathogen transmission, or it may act as a vessel for genetic variation. Under both situations, intermediate hosts make the management of zoonotic diseases a difficult task by regulating peak time and human infections at the time of the epidemic (Cui et al., 2017). Even with SARS-CoV-2, several captive animals, such as tigers and lions in the zoo, were reported to carry mild respiratory symptoms, which were later confirmed as SARS-CoV-2 infection by RT-PCR (Bartlett et al., 2021). Transmission of viruses from these captive animals to humans has been reported in several studies. SARS-CoV-2 was reported to cause infection among mink in farms and humans. It was concluded that this infection was initially introduced by humans and circulated among minks by an unknown mode of transmission (Oude Munnink et al., 2021).

Transmission of SARS-CoV-2 in a pet shop from Syrian hamsters to humans was also reported in the literature; however, the other animals in the pet shop were found to be negative for SARS-CoV-2 infection (Yen et al., 2022). Zooanthroponosis potential of SARS-CoV-2 implies its importance of viral persistence in animals and may create concerns for the development of management strategies against these infections, including vaccine development (Banerjee et al., 2021). The One Health approach looks at human infections while also considering animals and the environment. Therefore, the integration of multiple specializations in One Health has found potential in understanding the role of the intermediate host in several diseases. A recent study involving snail-transmitted parasitic diseases highlighted that the One Health approach must be considered before using snails as an alternative food to prevent snail-mediated parasitic diseases in humans (Pathak et al., 2023). Therefore, the One Health approach may play an important role in the management of zoonotic diseases along with the identification of their intermediate host and implementation of measures to prevent outbreaks caused due to these infections.

5. Implications of identifying intermediate hosts on public health strategies and policies

The global COVID-19 pandemic generated serious transformational impacts on both public health and policy. Governmental key sectors responded to the crisis alongside the private sectors and industry to minimize the risks and challenges to global health (Whitsel et al., 2023). Several massive challenges in social interactions, the economy, education, public services, biomedical research, public health, surveillance, data modernization, various prevention and containment policies, treatment strategies, and preparedness must be handled coordinately to overcome similar outbreaks. The global infection and mortality due to the pandemic reached 600 million cases and 6 million deaths (Stoto et al., 2023). These numbers provoked epidemiological scientists to trace the transmission routes and potential reservoirs of the virus.

Sequencing the SARS-CoV-2 genome during the early pandemic, followed by homology comparison, revealed bats as the natural hosts of this virus, sharing sequence homology of 96.2% and 93.3% with RaTG13 and RmYN02 (bat-coronaviruses), respectively (Zhou et al.,2020; Zhou H et al.,2020). Later, other possible wildlife intermediate hosts of SARS-CoV-2 were discovered, including pangolin (Dong et al., 2020), mink (Oreshkova et al., 2020), cats surrounding mink farms (Enserink 2020), and turtles (Liu et al., 2020), with a suggestion of receptor binding domain (RBD) interaction with the ACE2 receptor. High susceptibility to SARS-CoV-2 was observed experimentally with ferrets (Kim et al.,2020; Shi et al.,2020). Recent studies using algorithmic analysis of genetic sequences have found that the pattern of codon usage in SARS-CoV-2 is strikingly similar to that of snakes. This suggests that snakes might serve as possible intermediate hosts for the virus (Zhang et al.,2020). In frogs, relative synonymous codon usage (RSCU) is closer to the virus than in snakes (Zhang et al.,2020). However, viral RNA was also detected in monkeys, baboons, Chinese tree shrews, macaques, deer mice, marmoset, red foxes, skunk, and white-tailed deer, besides farmed (cattle, raccoon dog) and companion (several hamster species, cats, white rabbit, and mouse) animals (Meekins et al., 2021). Nevertheless, SARS-CoV-2 showed several mutations, and new variants continue to emerge, can escape immune responses, and infect either known or new intermediate hosts, creating novel animal reservoirs (Meekins et al., 2021).

5.1 Public health strategies and policies

It is probable that SARS-CoV-2 transmission between species, including humans to animals and vice versa or animal to animal, follows the same routes of transmission between individual human beings. It is challenging to identify the natural transmission upon the circulation of the viral genome beyond humans (Santini and Edwards 2020). However, human health depends on and is indirectly linked to both domestic and wild animals as part of the One Health theory. Consequently, ecosystem disturbance leading to zoonotic and/or reverse-zoonotic diseases occurred following the COVID-19 global pandemic (Munir et al., 2020).

Back to the origin of SARS-CoV-2, the virus was detected in 174 human cases around the market of Huanan seafood market in Wuhan City, China. In Wuhan markets, besides its provinces’ markets, fish, foxes, badgers, hedgehogs, hares, bamboo rats, and poultry in cages that were put on top of raccoon dogs are sold (Xiao et al.,2020; Worobey et al.,2022). These markets sold around 38 live species (meat or pet), including 31 protected species with a total of 36000 animals (Brüssow 2023), and on January 1^st, 2020, the market was closed. In this respect, the infected wildlife raccoon dogs, foxes, bats, and white-tailed deer are solitary mammals, which limits the potential circulation of the virus. In urban settings, on the contrary, colonies of mice and rats could be a public health concern. However, the risk of viral transmission, in the wilderness, for individuals, occupational personnel, and the general population is none/very low, very low, and none/very low, respectively (Boklund et al., 2021). Companion and farm animals are species at high risk of viral transmission with humans, especially cats, minks, and hamsters that live in households. These animals, when having contact with stray cats and other free animals, are considered a public health risk. When you look at it as a whole, many people in low and middle-income countries rely on wet markets that sell live wild and domestic animals as essential businesses. However, these animals are linked to over 60% of zoonotic diseases, with a staggering 72% of those coming from wildlife (Naguib et al.,2021).

Nevertheless, demands for wet market closure are still controversial between public health risks and food security for the poor. To solve this dilemma, researchers have tried first to precisely define and categorize the wet market into four animal selling types: 1) seafood/no live animals, 2) live domestic animals, 3) dead wild animals, and 4) live wild animals (Lin et al., 2021). Secondly, a political decision with strict controls should be released based on an analysis of risks, which are generally increased with evolution: mammals [bats > rodents, carnivores, and pangolins] > birds > reptiles, amphibians, and invertebrates (Brüssow 2024). Indeed, the implementation of such decisions varies between poor countries and developed countries. Next, the market size will define the level of contact between different species, customers, and vendors, and determine the degree of sanitization protocols. On 12 May 2021, the European Commission implemented the decision EU-2021/788 that lays down the rules and guidelines to monitor SARS-CoV-2 infections and report the infected cases in specific animal species, including minks and raccoon dogs. The legislative prerequisites comprised the events that trigger sampling, the sampling population (dead/sick/live animals), frequency of sampling (weekly/every 2 weeks), sample matrix (oropharyngeal swabs from live or dead animals), type of diagnostic test (viral genome), design of prevalence (5% prevalence with 95% confidence), and the amount number of required samples (Nielsen et al., 2023). However, the decision’s validity ended on 31^st March 2023, and it is no longer in force.

To date, and after the SARS-CoV-2 pandemic, the One Health definitions created by the WHO One Health High-Level Expert Panel (WHO-OHHLEP) and others, could not set the necessary principles and policies to control animal-imminent threats to human health (Su et al., 2024). The challenges to be considered are the equity of animals, humans, and plants, especially when humans’ health is jeopardized by zoonosis, the absence of early warning and surveillance systems, and the knowledge gap of SARS-CoV-2 emergence and adaptation in known or new intermediate hosts (Lefrançois et al., 2023). These gaps hinder the rapid determination and identification of zoonotic threats and impede the release of strategies to achieve efficient preparedness.

It is worth mentioning that short-lived action plans and declarations may be considered important to start a change. Moreover, factors such as poor resources and less experience in several sectors will hinder the implementation of One Health concept. Therefore, ambitious long-lived action plans comprising awareness, education, surveillance, sustainability, socio-behavior changes, training, and generous funding will be a start to apply a One Health program.

Early detection of SARS-CoV-2 in animals plays a role in preventing viral dissemination. Nevertheless, testing methods are used in surveillance studies, whether viral genome detection or serological protocols (Wernike et al. 2021). developed a multispecies ELISA test with 100% and 98.3% sensitivity and specificity, respectively, to detect SARS-CoV-2 in animals. The assay was based on a single RBD antigen and could detect the virus in hamsters, raccoon dogs, cattle, and ferrets. Another double antigen-based ELISA was able to detect anti-nucleocapsid antibodies from cats, minks, cattle, ferrets, horses, dogs, goats, and sheep (Hammer et al., 2021).

During pandemics like COVID-19, the One Health surveillance approach is compulsory to control the propagation of the zoonotic pathogen. The following Fig. 4 summarizes a potential surveillance system.

Potential One Health surveillance during the COVID-19 pandemic. The figure was created using Biorender.com.

6. Future research directions for investigating intermediate hosts for COVID-19

The following are some significant opportunities for further research on COVID-19 arising out of the natural selection of intermediate hosts.

The first opportunity is the research on the identification of intermediate host(s), such as determining potential mediators of transmission linking SARS-CoV-2 to humans from bats, which are believed to be the initial hosts (Zhao et al., 2020; Schindell et al., 2022) conducting extensive surveillance and sampling of wildlife species like mammals and birds in areas where there were early cases of COVID-19 (Martínez-Hernández et al., 2020), and using of advanced molecular techniques and serological assays to identify SARS-CoV-2 or related coronaviruses in possible intermediary hosts (Datta et al.,2021; Hayden et al.,2024).

The second opportunity is to understand transmission dynamics by examining how this virus spreads from the intermediate host(s) to man (Anderson et al., 2021). We should determine possible direct zoonotic transmission, as opposed to transmission through an intermediate host (Jo et al., 2021). Also, looking at the genetic material from humans infected with COVID-19 strains compared to possible intermediate host isolates could show special changes or adaptations that allow the virus to infect different species (Amoutzias et al.,2022).

The third opportunity includes ecological and environmental factors, since the ecological factors that affect spillover may include habitat fragmentation, loss of biodiversity, and wildlife trade, which should be studied (Glidden et al., 2021). These studies should also look at temperature, humidity, and other environmental conditions that influence viral persistence, survival, and adaptation within both the intermediate host(s) and humans themselves (Walther and Ewald 2004; Dash et al.,2021).

The fourth opportunity is the health approach, in which a multidisciplinary approach involving virologists, ecologists, epidemiologists, veterinarians, and public health experts would help understand complex interactions between people, animals, and the environment (Kelly et al., 2017). We should establish human-animal-environment health surveillance models to detect and monitor potential spillover events and new infectious diseases (Berrian et al., 2024).

The fifth opportunity is concerned with wildlife trade and animal markets, in which research is needed into the role of wildlife trade, both legal and illegal, as an avenue for introducing animal-borne infections (Aguirre et al., 2020). We also need to investigate the role of viral amplification and cross-species transmission in high-density animal markets. Better regulation and enforcement measures are necessary to reduce the risks associated with the wildlife trade or live animal markets (Roe et al., 2020).Finally, the public health interventions are based on evaluating non-pharmaceutical interventions like social distancing measures, face mask-wearing campaigns, and vaccination campaigns to prevent zoonotic spillovers as well as mitigate outbreaks in the future (Brüssow 2024).

7. Conclusions

This thorough review has investigated what we currently know about where SARS-CoV-2 comes from and how it spreads, the virus behind the COVID-19 pandemic. The evidence we have strongly points to a zoonotic origin for SARS-CoV-2, with bats being the most likely natural hosts. However, it is still not known which species served as an intermediate host, enabling the virus to jump from animals to humans. These detailed evolutionary analyses have helped us understand how SARS-CoV-2 may link to other bat coronaviruses over time. These suggest that SARS-CoV-2 emerged via recombination between various bat populations, leading to adaptation in humans. Nonetheless, there are no clear answers as to the specific intermediate hosts that enabled direct transmission from bats to humans. Therefore, we must immediately identify this missing link in the SARS-CoV-2 transmission chain. We must identify the intermediate host species and cross-species transmission modes to develop an effective strategy for preventing and controlling future outbreaks from animal-to-human contacts. Ultimately, uncovering this elusive “missing link” will necessitate ongoing, extensive surveillance of wildlife populations, particularly those with the highest diversity in bat species, and innovative genomic and serological techniques capable of identifying the initial intermediary host potentially responsible for the first human infection by SARS-CoV-2.

In summary, despite the significant advancements in understanding the origin of SARS-CoV-2, identifying its intermediate host continues to be an important information gap. The global research community must prioritize this challenge to better prepare themselves against emerging threats arising from human-animal contact.

Acknowledgement

The authors gratefully acknowledge and thank the Deanship of Graduate Studies and Scientific Research at Qassim University for financial support (QU-APC-2025).

CRediT authorship contribution statement

Sayed Sartaj Sohrab: Conceptualization, writing—original draft preparation, review, and editing. Rashid Mumtaz Khan: Writing—review and editing. Ashraf A. Tabll: Conceptualization, writing—review and editing. Mohd Suhail: Writing—review and editing. Abdul Arif Khan: Writing—review and editing. Amira M. Abouelella: Writing—review and editing. Nermeen T. Fahmy: Writing—review and editing. Esam I. Azhar: Writing—review and editing. Yasser E. Shahein: Writing—review and editing. All authors have read and approved the final version of the manuscript.

Declaration of competing interest

The authors declare that they have no competing financial interests or personal relationships that could have influenced the work presented in this paper.

Declaration of Generative AI and AI-assisted technologies in the writing process

The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.

Funding

This work was funded through the Deanship of Graduate Studies and Scientific Research at Qassim University for financial support (QU-APC-2025).

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1. Introduction

2. Challenges in determining the intermediate hosts of COVID-19

3. Potential intermediate hosts of SARS-CoV-2

3.1 Range of animal species as potential intermediate hosts of SARS-CoV-2
3.2 No intermediate host
3.3 Scientific evidence supporting or refuting the potential hosts
3.4 Genomic data to investigate the intermediate hosts of SARS-CoV-2

4. Importance of the One Health approach in understanding zoonotic disease

5. Implications of identifying intermediate hosts on public health strategies and policies

5.1 Public health strategies and policies

6. Future research directions for investigating intermediate hosts for COVID-19

7. Conclusions

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Emerged SARS-CoV-2 intermediate hosts: The missing links from One Health perspective

Abstract

Keywords

COVID-19

Coronaviruses

Economy

Emergence

Human health

Intermediate hosts

Spillover

1. Introduction

2. Challenges in determining the intermediate hosts of COVID-19

3. Potential intermediate hosts of SARS-CoV-2

3.1 Range of animal species as potential intermediate hosts of SARS-CoV-2

3.2 No intermediate host

3.3 Scientific evidence supporting or refuting the potential hosts

3.4 Genomic data to investigate the intermediate hosts of SARS-CoV-2

4. Importance of the One Health approach in understanding zoonotic disease

5. Implications of identifying intermediate hosts on public health strategies and policies

5.1 Public health strategies and policies

6. Future research directions for investigating intermediate hosts for COVID-19

7. Conclusions

Acknowledgement

CRediT authorship contribution statement

Declaration of competing interest

Declaration of Generative AI and AI-assisted technologies in the writing process

Funding

References

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