Curcumin as a natural potential drug candidate against important zoonotic viruses and prions: A narrative review.

Zoonotic diseases are major public health concerns and undeniable threats to human health. Among Zoonotic diseases, zoonotic viruses and prions are much more difficult to eradicate, as they result in higher infections and mortality rates. Several investigations have shown curcumin, the active ingredient of turmeric, to have wide spectrum properties such as anti-microbial, anti-vascular, anti-inflammatory, anti-tumor, anti-neoplastic, anti-oxidant, and immune system modulator properties. In the present study, we performed a comprehensive review of existing in silico, in vitro, and in vivo evidence on the antiviral (54 important zoonotic viruses) and anti-prion properties of curcumin and curcuminoids in PubMed, Google Scholar, Science Direct, Scopus, and Web of Science databases. Database searches yielded 13,380 results, out of which 216 studies were eligible according to inclusion criteria. Of 216 studies, 135 (62.5%), 24 (11.1%), and 19 (8.8%) were conducted on the effect of curcumin and curcuminoids against SARS-CoV-2, Influenza A virus, and dengue virus, respectively. This review suggests curcumin and curcuminoids as promising therapeutic agents against a wide range of viral zoonoses by targeting different proteins and signaling pathways.

Potent, specific MEPicides for treatment of zoonotic staphylococci.

Coagulase-positive staphylococci, which frequently colonize the mucosal surfaces of animals, also cause a spectrum of opportunistic infections including skin and soft tissue infections, urinary tract infections, pneumonia, and bacteremia. However, recent advances in bacterial identification have revealed that these common veterinary pathogens are in fact zoonoses that cause serious infections in human patients. The global spread of multidrug-resistant zoonotic staphylococci, in particular the emergence of methicillin-resistant organisms, is now a serious threat to both animal and human welfare. Accordingly, new therapeutic targets that can be exploited to combat staphylococcal infections are urgently needed. Enzymes of the methylerythritol phosphate pathway (MEP) of isoprenoid biosynthesis represent potential targets for treating zoonotic staphylococci. Here we demonstrate that fosmidomycin (FSM) inhibits the first step of the isoprenoid biosynthetic pathway catalyzed by deoxyxylulose phosphate reductoisomerase (DXR) in staphylococci. In addition, we have both enzymatically and structurally determined the mechanism by which FSM elicits its effect. Using a forward genetic screen, the glycerol-3-phosphate transporter GlpT that facilitates FSM uptake was identified in two zoonotic staphylococci, Staphylococcus schleiferi and Staphylococcus pseudintermedius. A series of lipophilic ester prodrugs (termed MEPicides) structurally related to FSM were synthesized, and data indicate that the presence of the prodrug moiety not only substantially increased potency of the inhibitors against staphylococci but also bypassed the need for GlpT-mediated cellular transport. Collectively, our data indicate that the prodrug MEPicides selectively and robustly inhibit DXR in zoonotic staphylococci, and further, that DXR represents a promising, druggable target for future development.

The kinetic profile of clinical and laboratory findings and treatment outcome of patients with toxocariasis.

OBJECTIVES: Human toxocariasis is a widespread zoonosis for which a chemotherapy decision and therapy effectiveness are difficult to determine. We aimed to investigate the kinetic profile of clinical and laboratory findings and treatment outcome of patients with toxocariasis in Vietnam. METHODS: The prospective study was conducted between October 2017 and June 2019. The diagnosis of toxocariasis was established based on clinical, laboratory (eosinophilia, raised IgE concentration) and serological (positive Toxocara IgG ELISA) evaluation as well as the exclusion of another helminthic co-infection. The patients were followed up after seven days, then one, three and six months after chemotherapy by thiabendazole. RESULTS: The study involved 80 patients with a mean age of 41.6 ± 15.2 years of whom 58.8% were female. At three and six months after chemotherapy, most patients demonstrated resolution of clinical signs and symptoms, eosinophil count and IgE concentration but not in the proportion of IgG seropositivity. Skin lesions and eosinophilia resolved earlier than the other symptoms (one month after treatment). About four-fifths of the patients were "cured" after three and six months of follow-up; 33.8% showed side effects to thiabendazole therapy but no severe events were reported. The most common adverse reaction was neurologic symptoms followed by gastrointestinal or skin manifestations which lasted as long as 4 days. CONCLUSIONS: In toxocariasis patients, cutaneous manifestations and eosinophilia resolve more rapidly than other clinical and laboratory findings while IgG titre has a very slow kinetic after therapy. Thiabendazole seems to be a potential alternative for the treatment of human toxocariasis.

Effectiveness of doxycycline for the treatment of zoonotic cutaneous leishmaniasis in vivo.

There are available data on in vivo studies of monotherapy of zoonotic cutaneous leishmaniasis with some antibacterial drugs (doxycycline) and their comparison with meglumine antimoniate (glucantime). We used golden Syrian hamsters as a laboratory model. Experimental groups were formed, each of which was treated with one of the tested drugs. Infection of animals was carried out with Leishmania major promastigotes. We selected highly virulent strains of L. major culture isolated from human ulcers or rodents. Meglumine antimoniate monotherapy and doxycycline monotherapy are quite effective and do not differ by the 30th day of their use in such indicators as the average degree of local damage and the average number of Leishmania in the lesions. The main differences were recorded in terms of average body weight gain and average clinical recovery in favour of doxycycline. Leishmania in the lesion on the 60th day were completely absent in treatment with doxycycline. The experiment proved the effectiveness of doxycycline monotherapy: Leishmania in the lesions were absolutely absent by the end of the treatment.

In vitro antifungal susceptibility patterns of Trichophyton benhamiae complex isolates from diverse origin.

BACKGROUND: Species from the Trichophyton benhamiae complex are mostly zoophilic dermatophytes which cause inflammatory dermatophytosis in animals and humans worldwide. OBJECTIVES: This study was purposed to (a) to identify 169 reference and clinical dermatophyte strains from the T benhamiae complex species by molecular method and adhering to the newest taxonomy in the complex (b) to evaluate the in vitro antifungal susceptibility profile of these strains against eight common and new antifungal agents that may be used for the treatment of dermatophytosis. METHODS: All isolates, mainly originated from Europe but also from Iran, Japan and USA, were subjected to ITS-rDNA sequencing. The in vitro antifungal susceptibility profiles of eight common and new antifungal drugs against the isolates were determined by CLSI M38-A2 protocol and according to microdilution method. RESULTS: Based on the ITS-rDNA sequencing, T benhamiae was the dominant species (n = 102), followed by T europaeum (n = 29), T erinacei (n = 23), T japonicum (n = 10), Trichophyton sp (n = 4) and T eriotrephon (n = 1). MIC ranges across all isolates were as follows: luliconazole: 0.0002-0.002 µg/ml, terbinafine: 0.008-0.125 µg/ml, efinaconazole: 0.008-0.125 µg/ml, ciclopirox olamine: 0.03-0.5 µg/ml, itraconazole: 0.06-2 µg/ml, griseofulvin: 0.25-4 µg/ml, amorolfine hydrochloride: 0.125-4 µg/ml and tavaborole: 1-16 µg/ml. CONCLUSION: Luliconazole, efinaconazole and terbinafine were the most potent antifungals against T benhamiae complex isolates, regardless of the geographic locations where strains were isolated. These data might help dermatologists to develop effective therapies for successful treatment of infections due to T benhamiae complex species.

Zoonotic transmission of Teladorsagia circumcincta and Trichostrongylus species in Guilan province, northern Iran: molecular and morphological characterizations.

BACKGROUND: Parasitic trichostrongyloid nematodes have a worldwide distribution in ruminants and frequently have been reported from humans in Middle and Far East, particularly in rural communities with poor personal hygiene and close cohabitation with herbivorous animals. Different species of the genus Trichostrongylus are the most common trichostrongyloids in humans in endemic areas. Also, Ostertagia species are gastrointestinal nematodes that mainly infect cattle, sheep and goats and in rare occasion humans. The aim of the present study was to identify the trichostrongyloid nematodes obtained from a familial infection in Guilan province, northern Iran, using morphological and molecular criteria. METHODS: After anthelmintic treatment, all fecal materials of the patients were collected up to 48 h and male adult worms were isolated. Morphological identification of the adult worms was performed using valid nematode keys. Genomic DNA was extracted from one male worm of each species. PCR amplification of ITS2-rDNA region was carried out, and products were sequenced. Phylogenetic analysis of the nucleotide sequence data was performed using MEGA 6.0 software. RESULTS: Adult worms expelled from the patients were identified as T. colubriformis, T. vitrinus and Teladorsagia circumcincta based on morphological characteristics of the males. Phylogenetic analysis illustrated that each species obtained in current study was placed together with reference sequences submitted to GenBank database. CONCLUSIONS: The finding of current study confirms the zoonotic aspect of Trichostrongylus species and T. circumcincta in inhabitants of Guilan province. The occurrence of natural human infection by T. circumcincta is reported for the first time in Iran and the second time in the world.

Diagnosis of Streptococcus suis Meningoencephalitis with metagenomic next-generation sequencing of the cerebrospinal fluid: a case report with literature review.

BACKGROUND: Streptococcus suis meningoencephalitis is a zoonotic disease that mostly infects slaughterhouse workers. Rapid diagnosis of Streptococcus suis meningoencephalitis is critical for effective clinical management of this condition. However, the current diagnostic techniques are not effective for early diagnosis of this condition. To the best of our knowledge, the use of cerebrospinal fluid metagenomic next generation sequencing in the diagnosis of Streptococcus suis meningoencephalitis has been rarely reported. CASE PRESENTATION: Here, we report a case of Streptococcus suis meningoencephalitis in a 51-year-old female patient. The patient had a history of long-term contact with pork and had a three-centimeter-long wound on her left leg prior to disease onset. Conventional tests, including blood culture, gram staining and cerebrospinal fluid culture, did not reveal bacterial infection. However, Streptococcus suis was detected in cerebrospinal fluid using metagenomic next generation sequencing. CONCLUSIONS: Metagenomic next generation sequencing is a promising approach for early diagnosis of central nervous system infections. This case report indicates that cases of clinical meningeal encephalitis of unknown cause can be diagnosed through this method.

Meningoencephalitis, coronary artery and keratitis as an onset of brucellosis: a case report.

BACKGROUND: Brucellosis is a zoonotic disease caused by brucella. It has been an increasing trend in recent years (Wang H, Xu WM, Zhu KJ, Zhu SJ, Zhang HF, Wang J, Yang Y, Shao FY, Jiang NM, Tao ZY, Jin HY, Tang Y, Huo LL, Dong F, Li ZJ, Ding H, Liu ZG, Emerg Microbes Infect 9:889-99, 2020). Brucellosis is capable to invade multiple systems throughout the body, lacking in typical clinical manifestations, and easily misdiagnosed and mistreated. CASE PRESENTATION: We report a case of a male, 5-year-and-11-month old child without relevant medical history, who was admitted to hospital for 20 days of fever. When admitted to the hospital, we found that he was enervated, irritable and sleepy, accompanied with red eyes phenomenon. After anti-infection treatment with meropenem, no improvement observed. Lumbar puncture revealed normal CSF protein, normal cells, and negative culture. Later, doppler echocardiography suggested coronary aneurysms, and incomplete Kawasaki Disease with coronary aneurysms was proposed. The next day, brucellosis agglutination test was positive. Metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid suggested B.melitensis, which was confirmed again by blood culture. The child was finally diagnosed as brucellosis with meningocephalitis, coronary aneurysm and keratitis. According to our preliminary research and review, such case has never been reported in detail before. After diagnosis confirmation, the child was treated with rifampicin, compound sulfamethoxazole, and ceftriaxone for cocktail anti-infection therapy. Aspirin and dipyridamole were also applied for anticoagulant therapy. After medical treatment, body temperature of the child has reached normal level, eye symptoms alleviated, and mental condition gradually turned normal. Re-examination of the doppler echocardiographic indicated that the coronary aneurysm was aggravated, so warfarin was added for amplification of anticoagulation treatment. At present, 3 months of follow-up, the coronary artery dilatation gradually assuaged, and the condition is continued to alleviate. CONCLUSION: Brucellosis can invade nervous system, coronary artery, and cornea. Brucellosis lacks specific signs for clinical diagnosis. The traditional agglutination test and the new mNGS are convenient and effective, which can provide the reference for clinical diagnosis.

Highlighting the role of veterinary pharmacists in zoonotic diseases including COVID-19.

Veterinary pharmacy is an often unknown and therefore, underrepresented career path for pharmacists. Uniquely, pharmacists-even untrained in veterinary medicine-are the only health professionals legally allowed to provide care for human and nonhuman patients. The 2019 coronavirus disease (COVID-19) pandemic is a peculiar situation that, not only highlights veterinary pharmacy as a career path, but stresses the role veterinary pharmacists, trained in both human and veterinary medicine, can play in zoonotic diseases. Specialized training in veterinary medicine allows the pharmacist to serve as a resource for both physicians as well as veterinarians during zoonotic events by helping to ascertain feasibility of therapeutic options given the species. In addition, veterinary pharmacists involved in translational research would be vital for the drug development process as they would be aware of biologic nuances between the species and how they may affect the ultimate therapeutic outcome.

Francisella tularensis Periprosthetic Joint Infections Diagnosed with Growth in Cultures.

Tularemia caused by Francisella tularensis is a zoonotic infection of the Northern Hemisphere that mainly affects the skin, lymph nodes, bloodstream, and lungs. Other manifestations of tularemia are very rare, especially those with musculoskeletal involvement. Presenting in 2016, we diagnosed two cases of periprosthetic knee joint infections (PJI) caused by Francisella tularensis in Europe (one in Switzerland and one in the Czech Republic). We found only two other PJI cases in the literature, another knee PJI diagnosed 1999 in Ontario, Canada, and one hip PJI in Illinois, USA, in 2017. Diagnosis was made in all cases by positive microbiological cultures after 3, 4, 7, and 12 days. All were successfully treated, two cases by exchange of the prosthesis, one with debridement and retention, and one with repeated aspiration of the synovial fluid only. Antibiotic treatment was given between 3 weeks and 12 months with either ciprofloxacin-rifampin or with doxycycline alone or doxycycline in combination with gentamicin. Zoonotic infections should be considered in periprosthetic infections in particular in culture-negative PJIs with a positive histology or highly elevated leukocyte levels in synovial aspiration. Here, we recommend prolonging cultivation time up to 14 days, performing specific PCR tests, and/or conducting epidemiologically appropriate serological tests for zoonotic infections, including that for F. tularensis.

Severe infections due to Francisella tularensis ssp. holarctica in solid organ transplant recipient: report of two cases and review of literature.

BACKGROUND: Tularemia is a rare zoonotic infection caused by bacterium Francisella tularensis. It has been well described in immunocompetent patients but poorly described in immunocompromised patients notably in solid organ transplant recipients. CASE PRESENTATIONS: We report here two cases of tularemia in solid organ transplant recipients including first case after heart transplant. We also carried out an exhaustive review of literature describing characteristics of this infection in solid organ transplant recipients.

Acute pancreatitis and vasoplegic shock associated with leptospirosis - a case report and review of the literature.

BACKGROUND: Leptospirosis or Weil's disease is caused by pathogenic spirochete bacteria called Leptospira. It is considered the most common zoonosis in the world and is usually transmitted by urine of rodents and dogs with an incubation time of 7-14 days. The clinical spectrum ranges from a subclinical infection to a fulminant septic course. CASE PRESENTATION: Here, we report the case of a German patient with acute pancreatitis associated with Leptospira interrogans causing fulminant septic shock. The patient was successfully treated with intravenous antibiotics and left the hospital fully recovered after 18 days. CONCLUSIONS: To our knowledge, this is the first case of leptospirosis with acute pancreatitis as the leading clinical manifestation in Central Europe. Serologic and molecular genetic tests for leptospirosis should be considered, if no other causes for pancreatitis can be identified.

Trichophyton mentagrophytes - a new genotype of zoophilic dermatophyte causes sexually transmitted infections.

BACKGROUND: A new genotype of the zoophilic fungal species Trichophyton (T.) mentagrophytes was recently described in two studies. It was isolated from three patients who had visited Southeast Asia and one patient who had visited Egypt. In contrast to these studies, we have observed a number of cases with the dimensions of an epidemic outbreak. PATIENTS AND METHODS: At the University Hospital Charité Berlin, 43 patients, mostly suffering from highly inflammatory, painful and persistent infections of the pubogenital region were observed between January 2016 and July 2017. Mycological examination was performed with fungal culture and sequencing of the ITS (internal transcribed spacer) region of the ribosomal DNA. Three additional genomic regions were spot-checked. RESULTS: In 37 of the cases, a new genotype of T. mentagrophytes (referred to here as T. mentagrophytes VII) was isolated as the etiological agent, and sequencing revealed identical sequences for all isolates. Most of the infected patients had no history of travel, and only two patients reported contact with animals. CONCLUSIONS: The new genotype clustered phylogenetically among the strains of the zoophilic species T. mentagrophytes with four different DNA markers. While human-to-human transmission of zoophilic dermatophytes is rare, transmission via sexual contact seemed to be quite effective here.

Diagnosis and treatment of Bartonella endocarditis.

The Bartonella genus comprises more than 20 species of Gram-negative rods which are difficult to culture. These are facultative intracellular bacteria. Humans are reservoir hosts for B. quintana and B. bacilliformis or accidental hosts for other species. Bartonella is a cause of zoonosis. Bartonella infection can be completely asymptomatic or can be linked to various conditions. Our experience with Bartonella endocarditis from 2012-2017 is presented. The most effective diagnostic method for Bartonella endocarditis is PCR detection of DNA of the pathogen from excised valve tissue. The European Society of Cardiology (ESC) in the guidelines from 2015 recommends the combination doxycycline gentamycin for the treatment of Bartonella endocarditis.

Equine Granulocytic Anaplasmosis 28 years later.

Equine granulocytic anaplasmosis (EGA) is an important tick borne disease of equines that is caused by Anaplasma phagocytophilum (A. phagocytophilum). The etiological agent has veterinary as well as public health importance because of its zoonotic nature. A. phagocytophilum causes an acute illness in equines with loss of appetite, lethargy, hemorrhages and lameness. Clinically, EGA is diagnosed upon examination of morulae within neutrophils especially granulocytes in the blood. The best diagnostic tool for the detection of EGA is Polymerase chain reaction (PCR). Previous studies suggested that EGA is a self-limiting disease and tetracycline therapy is considered as a best treatment regimen. There is no comprehensive summary on the occurrence and distribution of the infection at global level. Therefore, we intended to provide a comprehensive summary on the prevalence and epidemiology of EGA in different areas of the world. It includes mapping the global distribution of EGA in different areas of the world to identify the endemic regions which may be a source of potential disease outbreak. For this purpose, the published data from 1990 to 2018 on EGA was reviewed and collected by electronic literature search of five databases including Google, Google Scholar, Science Direct, PubMed and Web of Science.

Cephalosporin-resistant Escherichia coli isolated from farm workers and pigs in northern Vietnam.

OBJECTIVE: Antimicrobial-resistant bacteria may be transmitted between farm workers and livestock. This study aimed to determine and compare the prevalence and the genetic determinants of cefotaxime-resistant and ESBL-producing Escherichia coli in faecal isolates from workers and pigs at 100 farms in northern Vietnam. METHODS: Farmers were interviewed about antimicrobial usage in livestock. Escherichia coli isolated on MacConkey agar containing 2 mg/l of cefotaxime (CTX) were tested for susceptibility to different cephalosporins by disc diffusion and screened for occurrence of ESBL-encoding genes by PCR. RESULTS: Antimicrobial usage was widespread and included classes regarded of critical or high importance in human medicine. Dosages were 0.5-2 times higher than recommended, and antimicrobials were often administered right until slaughter. Prevalence of CTX-resistant E. coli was 86% in farm workers and 89% in pigs. In 76% of farms, CTX-resistant E. coli were shared by pigs and farm workers. ESBL-producing E. coli were detected from pigs and workers at 66 and 69 farms, respectively. The ESBL phenotype was mainly mediated by CTX-M and to a lesser extent by TEM. Occurrence of blaCTX-M was similar in E. coli from pigs (66.7%) and humans (68.5%). CONCLUSION: The high occurrence of ESBL-producing E. coli in pig farmers and pigs could present a risk for spillover of these bacteria from pig farms into the community. Genomic studies are needed to elucidate reservoirs and transmission routes of ESBL-producing E. coli at livestock farms.

Fungal infections in animals: a patchwork of different situations.

The importance of fungal infections in both human and animals has increased over the last decades. This article represents an overview of the different categories of fungal infections that can be encountered in animals originating from environmental sources without transmission to humans. In addition, the endemic infections with indirect transmission from the environment, the zoophilic fungal pathogens with near-direct transmission, the zoonotic fungi that can be directly transmitted from animals to humans, mycotoxicoses and antifungal resistance in animals will also be discussed. Opportunistic mycoses are responsible for a wide range of diseases from localized infections to fatal disseminated diseases, such as aspergillosis, mucormycosis, candidiasis, cryptococcosis and infections caused by melanized fungi. The amphibian fungal disease chytridiomycosis and the Bat White-nose syndrome are due to obligatory fungal pathogens. Zoonotic agents are naturally transmitted from vertebrate animals to humans and vice versa. The list of zoonotic fungal agents is limited but some species, like Microsporum canis and Sporothrix brasiliensis from cats, have a strong public health impact. Mycotoxins are defined as the chemicals of fungal origin being toxic for warm-blooded vertebrates. Intoxications by aflatoxins and ochratoxins represent a threat for both human and animal health. Resistance to antifungals can occur in different animal species that receive these drugs, although the true epidemiology of resistance in animals is unknown, and options to treat infections caused by resistant infections are limited.

Lactobacillus rhamnosus reduces parasite load on Toxocara canis experimental infection in mice, but has no effect on the parasite in vitro.

Human toxocariasis is a neglected global parasitic zoonosis. The efficacy of drug treatment for this disease has been hindered by the biological complexity of the main etiological agent, the nematode Toxocara canis. Experimental studies have shown the potential of probiotics to promote a reduction in the parasite load of T. canis larvae. This study aimed to evaluate the effect of probiotic Lactobacillus rhamnosus ATCC 7469 on the parasite load of BALB/c mice with acute toxocariasis and evaluate the direct effect of this probiotic on T. canis larvae in vitro. In vivo administration of probiotics reduced the parasite load of T. canis larvae by 53.3% (p = 0.0018) during the early stage of infection in mice. However, when analyzed in vitro, it was observed that the probiotic did not present a deleterious effect on the larvae, as approximately 90% of these remained viable. These results demonstrate the potential of the probiotic L. rhamnosus in the reduction of T. canis larvae in BALB/c mice and suggest it could be used as an alternative means for the controlling of visceral toxocariasis. However, further studies are required to elucidate the mechanisms of action promoted by this probiotic.

Respiratory diphtheria due to Corynebacterium ulcerans transmitted by a companion dog, Italy 2014.

A serious respiratory tract infection due to Corynebacterium ulcerans was observed in a 70-year-old woman. Clinical presentation included pseudomembranes in the upper respiratory tract and lung involvement. C. ulcerans was recovered from the nose of the patient's dog. Both dog's and patient's isolates belonged to Sequence Type 331.

Identification of human neutralizing antibodies against MERS-CoV and their role in virus adaptive evolution.

The newly emerging Middle East Respiratory Syndrome coronavirus (MERS-CoV) causes a Severe Acute Respiratory Syndrome-like disease with ∼43% mortality. Given the recent detection of virus in dromedary camels, zoonotic transfer of MERS-CoV to humans is suspected. In addition, little is known about the role of human neutralizing Ab (nAb) pressure as a driving force in MERS-CoV adaptive evolution. Here, we used a well-characterized nonimmune human Ab-phage library and a panning strategy with proteoliposomes and cells to identify seven human nAbs against the receptor-binding domain (RBD) of the MERS-CoV Spike protein. These nAbs bind to three different epitopes in the RBD and human dipeptidyl peptidase 4 (hDPP4) interface with subnanomolar/nanomolar binding affinities and block the binding of MERS-CoV Spike protein with its hDPP4 receptor. Escape mutant assays identified five amino acid residues that are critical for neutralization escape. Despite the close proximity of the three epitopes on the RBD interface, escape from one epitope did not have a major impact on neutralization with Abs directed to a different epitope. Importantly, the majority of escape mutations had negative impacts on hDPP4 receptor binding and viral fitness. To our knowledge, these results provide the first report on human nAbs against MERS-CoV that may contribute to MERS-CoV clearance and evolution. Moreover, in the absence of a licensed vaccine or antiviral for MERS, this panel of nAbs offers the possibility of developing human mAb-based immunotherapy, especially for health-care workers.