We detected PMMoV RNA by real-time PCR in stool from 22 of 304 (7.2%) adult patients and 1 of 208 children who received care in public hospitals. The present study therefore confirms the recent finding by Zhang et al.
who identified PMMoV as the major RNA virus in human stool in a metagenomic study 
. However, we found a much lower prevalence of PMMoV RNA-positive stool by real-time PCR among adult patients than Zhang et al.
, who detected the viral genome in 12 of 18 fecal samples (66.7%) using RT-PCR. This difference might be explained either by a lower sensitivity for real-time PCR or the lower exposure to PMMoV in our patients. We recovered PMMoV RNA sequences from 57% of food products containing pepper or spice and purchased from grocery stores in Marseille (southeastern France), indicating that these products represent a common source of viruses through ingestion. In addition, in food products and patient's stool, we could visualize by electron microscopy complete viruses whose shape and size are consistent with PMMoV and that reacted with PMMoV-specific antibodies in the immunogold staining experiments. Moreover, 46 new PMMoV sequences corresponding to two regions of the viral genome were recovered from food products or patients' stool. Four phylogenetic clusters were identified, and one of them (II-1) included sequences from both patients and a putative food source. Furthermore, three PMMoV RNA-positive food products were found to contain virus particles infectious to host plants.
We also identified statistically significant differences in the occurrence of fever, abdominal pains, and pruritus and the detection of specific immune responses to PMMoV in the case-control study. We, therefore, believe that we provide the first evidence that plant viruses may cause disease in humans. Fever and abdominal pains, which were significantly more common in PMMoV-positive patients (39% for both clinical features) than in patients with PMMoV-negative stool (13% and 7%, respectively), were also present in the only PMMoV RNA-positive child. These symptoms might not be caused by PMMoV but by consumption of spicy food. Otherwise, they may be fortuitously related to an associated unknown infectious agent or to an allergic or toxic cofactor. Nevertheless, the presence of a specific immune response to PMMoV reinforces the hypothesis that this plant virus was the cause of the symptoms in these patients. Indeed, anti-PMMoV IgM antibodies were detected in all PMMoV-positive patients, significantly more frequently than in the controls. The concurrent detection of PMMoV RNA and antibodies to PMMoV indicates that this virus is not a neutral component of the human gut flora. On the contrary, our findings suggest that PMMoV may infect humans and cause clinical symptoms. We believe that these preliminary data may prompt further studies on the pathogenic role of PMMoV in humans. Finally, the higher prevalence of PMMoV RNA among patients who received care in Dermatology Units deserves further attention, as it was high (35%).
To date, plant viruses and vertebrate viruses are believed to exist in two distinct and non overlapping biological niches, and they are not known to share common hosts in the plant or animal kingdoms 
. Therefore, to date, plant viruses have not been described as pathogens for vertebrates or humans or known even to infect them 
. This paradigm is underscored by the growing body of data about the use of plant virus–based vaccines, which are considered as safe tools that might be useful in treating chronic viral infections and cancer in the future 
. However, the boundaries between plants and animals might not be so hermetical for plant viruses, and, to our knowledge, no experimental model has been described that would allow us to rule out a pathogenic role for plant viruses in vertebrates. The recent work of Zhang et al. challenged this dogma, as it was neutral, technology-driven research that was not trying to confirm a former hypothesis 
. That work identified plant viruses as the most common viral inhabitants of the human gut flora, PMMoV being the most prevalent. In addition, a recent study demonstrated that PMMoV is widespread in wastewater from the United States of America (USA), at concentrations ranging between 8.0×105
. Beyond these findings, our results, together with previous data, suggest that the relationship between plant viruses and animals may deserve further re-evaluation using modern microbiologic tools (). The oral administration of Cowpea severe mosaic virus
, another plant virus, has been previously shown to induce a durable and systemic immune response in mice without requiring the co-administration of an adjuvant 
, and similar results have been observed in mice using Alfalfa mosaic virus
and chimeric plant virus particles 
. In addition, some plant viruses can replicate in insect tissues, as illustrated by Tomato spotted wilt virus
and Maize rayado fino virus 
. Furthermore, a reduction in the lifespan and fecundity of insects (Bemisia tabaci
) during infection with Tomato yellow leaf curl virus
has been previously observed, indicating that this plant virus had some features of an insect pathogen 
. It has been also suggested, based on viral sequence analysis, that during evolution, plant-infecting viruses (previously known as plant circoviruses and recently reclassified in the genus Nanovirus
) switched hosts to infect a vertebrate and then recombined with a vertebrate-infecting virus 
. Moreover, it has been shown recently that Tomato spotted wilt virus
could replicate in two human cell lines, HeLa and diploid fibroblasts 
. This virus is one of the most important plant pathogens worlwide, and it causes mild infection on its main insect vector, Frankliniella occidentalis
, in which it induces a strong immune response 
. Finally, the possible involvement of plant viruses in human diseases was questioned several decades ago. Indeed, culturable Tobacco mosaic virus
could be recovered from sputum and thoracentesis fluids obtained from cigarette smokers with a history of pulmonary disease, including lung cancer 
. Taken together, these experimental data, coupled with the previous results reported by Zhang et al.
and our findings, favor the hypothesis of a pathogenic role for PMMoV. It should be highlighted that PMMoV, like other tobamoviruses, are known to be extraordinarily resistant to heat and desiccation 
. Moreover, although this deserves to be investigated in further studies, the viability and infectivity to host plants were evidenced for PMMoV recovered from food products in the present study and from stools in Zhang et al.'s study 
. Additionally, we visualized complete viral particles in stool by electron microscopy.
Summary of postulates and findings about interactions of PMMoV with the host immune system, its replication in non-plant tissues, and its potential link with clinical signs.
In summary, we confirmed that humans may carry a high PMMoV load, likely acquired from food products, and we documented that PMMoV might not only be a common inhabitant of the human gut but may also interact with the human immune system and cause clinical symptoms. These results should prompt further studies to re-evaluate whether or not plant viruses, including PMMoV, may have a pathogenic role in humans.