Review Article

A Literature Review of Neospora caninum Infection in Humans

Background

Neosporosiscaused by Neospora caninum,a Toxoplasma-like parasite belonging to obligate intracellular coccidian from the Toxoplasmatidae family, is a commonparasitic disease in animals around the world (1). The Neospora infection was first distinguished in six Norwegian Boxer puppies in 1984. Neuromuscular problems such as encephalitis and myositis were the predominant clinical findings in all sick dogs (2). This parasite was misdiagnosed by Toxoplasma gondii before its introduction (3).

Meanwhile, a wide range of animals and birds are definitive and intermediate hosts for N. caninum. Domestic dogs and dairy cattle are commonly definitive and intermediate hosts in the life cycle of this parasite, respectively (3). Interestingly, dogs may simultaneously play a role in both final and intermediate hosts (4). The infection has been accounted for various species of warm-blooded vertebrates, some of which may serve as intermediate hosts in domestic and sylvatic cycles (3,4).

Neosporosis is a serious disease in animals. The significant role of the disease in abortion and other reproductive failures in cattle is clear (4,5). The annual economic losses related to the Neospora infection have been estimated at more than US$1.3 billion on a global scale (6). The detection of this infection is possible by different laboratory methods such as serology and molecular biology in animals and humans (1,4).

Currently, there is no report on clinical neosporosis in humans (7). Regarding the close phylogenetic relationship between N. caninum and T. gondii, as well as a wide range of intermediate hosts, the possibility of the Neosporainfection in humans is undeniable (8), and the pathology, immunology, and epidemiology aspects of the infection in humans must be further studied accordingly (9). N. caninum is an important cause of fatal infections through experimentally transferring to pregnant cases with the lesions closely resembling those caused by congenital toxoplasmosis (10). A different level of antibodies to the Neospora infection have been detected in humans’ sera (3,4). N. caninum was successfully cultured in various cell lines of humans. Furthermore, Rhesus monkeys (Macaca mulatta) were experimentally infected with N. caninum (11,12). Barr et al(11) demonstrated the vertical transmission of this parasite in monkeys, reinforcing the concern about the zoonotic potential of the disease. In this regard, the present study mainly aimed to first review the global investigations on the Neospora infection in humans.

Methods

All published peer-reviewed articles (from January to April 2021) were searched in some English databases (e.g., Google Scholar, ScienceDirect, Scopus, PubMed, and ProQuest) using different keywords including “Neospora”, “Neospora caninum”, “neosporosis”, “epidemiology”, “prevalence”, “anti-Neospora antibodies”, and “human”. All articles by reputable journals (ISI and/or Scopus) were included in this study.

Results

All data on the Neospora infection in humans are tabulated in Table 1 (8-10,12-21). Based on the results, 13 articles were found on the Neospora infection in humans. Antibodies to the Neospora infection were between 0 and 37.7%. It was relatively high in HIV-positive individuals (26.6% and 37.7%) versus other cases. There were two studies on this subject based on molecular biology techniques (0-1%).

Discussion

Zoonotic diseases are a developing concern because of their novel and erratic nature, as well as their fast circulation and ability to emerge anywhere. To design the Lunch Control Programs of zoonosis, it is essential to obtain knowledge on the risk factors and epidemiology of diseases in animals (22). Most clinical manifestations of neosporosis in animals are similar to those of toxoplasmosis (1). The tachyzoite form of the parasite may be disseminated in various tissues (i.e. blood, placenta, and amniotic fluid). Although no convincing evidence exists indicating that N. caninum effectively infects humans, there is still a concern and ambiguity for transmitting the infection (23). Serologic findings confirmed humans’ exposure to this parasite, especially in immunodeficiency people (Table 1) although complementary works are essential to determine the extent and significance of humans’ exposure (15). Neosporosis is yet an uncertain issue in medical infectious diseases (4,7). Regarding the high frequency of the Neospora infection in the transplacental transmission mode of cows (up to 90%), and the close similarity with the T. gondii infection, the possibility of Neospora posing a risk for pregnant women should receive special attention (24).

In an experimental work by Carvalho et al (25), the transplacental transmission and teratogenic lesions of the N. caninum infection were found in non-human primates parallel to histopathological lesions caused by T. gondii. Additionally, humans’ cervical cells and trophoblasts were successfully infected by the tachyzoite form of N. caninum in vitro. The differences in susceptibility to the infection, cytokine production (type and rate), and cell viability were calculated in this evaluation (25). Some studies also focused on humans’ neosporosis in the world. There is a limit of knowledge on epidemiology, pathology and the zoonotic aspect of Neospora-infection. The overall prevalence of the Neosporainfection was estimated 17.14% (95% CI: 15.25-19.10%), 20% (95% CI: 18-21%), and 48.4% (95% CI: 47.5-49.3%) in dogs, cattle, and buffaloes, respectively, and 13.46% (95% CI: 10.26-17.42%) in horses and donkeys in different countries (26-29).

Nam et al (13) first reported the Neospora infection in humans from Korea. In this work, the seroprevalence rate was 4.6% (13/282) in blood donors. In Brazil, antibodies to the Neospora infection were detected between 26.6% and 37.7% in HIV-positive people, as well as 18%, 10.5%, and 5% in patients with neurological signs, farmworkers, and newborn children, respectively (10,16,17). Moreover, no antibodies to the Neospora infection were found in women with a history of abortion and genitally failures in serological studies by Petersen et al (8) and Trees and Williams (18). On the other hand, the genomic DNA of Neospora was not detected in cases (n = 600) with clinical manifestations in favor of toxoplasmosis and negative for the T. gondii infection in molecular evaluations. According to their opinions, there was an unlikely opportunistic zoonotic agent (21).

The seroprevalence rate of infection to N. caninum and T. gondii in pregnant women was 24.3% and 26.8% using the immunofluorescence antibody test (IFAT), respectively (9). Two samples of the cord blood from Neospora-seropositive humans were positive using the molecular biology assay. Direct sequencing showed 98-99% homology compared to the reported strains from other countries. Based on the findings, tissue cysts and/or inflammatory infiltrate lesions related to the Neospora infection were not observed in histopathology examinations. There was a statistically significant association between seropositivity to theNeosporainfection and the presence of domestic animals (P = 0.039), as well as dogs (P = 0.038) in the studied regions. This research acquired significant findings in terms of the Neospora infection in humans based on both serology and molecular biology tests (9).

With regard to the close biologic similarity between N. caninum and T. gondii, along with the possible presence of the parasite in immunocompromised individuals, it has been speculated that the Neospora infection can be transmitted to humans (8,10). According to Graham et al (14), the presence of N. caninum in the cotyledonary villi of the bovine placenta can be a risk option and a possible source for humans’ infection, especially in farmers and veterinarians. The infected dogs easily contaminate the environment life of humans by excreting the parasite oocytes through their feces (5). Due to the close contact of humans with dogs (pet dogs and sheepdogs are common in urban and rural regions, respectively), the chance of humans’ exposure to the Neosporainfection is extremely high (15). The assessment of tissue liquids in individuals with immune deficiencies and fetuses suspected with toxoplasmosis during pregnancy could confirm that a subpopulation of the patients were infected with N. caninum (15). A significant association was detected between the seroprevalence of N. caninum and T. gondii infections in HIV-positive people and those with neurological problems (10). In a report by Graham et al (14), the Neospora-seropositive sera samples were negative for the T. gondii infection, which was not responsible for cross-reactivity. No cross-reactivity was found between N. caninum and T. gondii infections in serology examinations with IFAT (4). However, using laboratory methods with high sensitivity and specificity is suggested for avoiding false-positive and false-negative reactions.

Different options such as the main purpose for designing the research, sampling and sample size, and laboratory diagnostic methods, as well as climatic and environmental factors of the studied location are crucial in the reported results in Table 1 (24). The sporulation (time and rate) and the survival of the oocysts in the environment with different temperature and air humidity rates are of various types (3).

A wide range of serological diagnostic methods with different sensitivity and specificity rates have been used in previous studies (8,10,12,13). An investigation is recently conducted based on the molecular biology technique (21). The sensitivity of enzyme-linked immunosorbent assay and specificity of IFAT are higher compared to other serologic methods (3,4). Toxoplasma and Neospora were classified in the same family (Toxoplasmatidae). Thus, the rate of infections and clinical manifestations should be high in immunosuppressed individuals. For this reason, the seroprevalence rate of the Neospora infection was high (26.6% and 37.7%) in HIV-positive humans in Brazil (10,17).

Conclusions

This literature review is the first one to focus on the Neospora infection in humans. It was found that the presence of antibodies to N. caninum is due to humans’ exposure to the parasite. A comprehensive and systematic research study is essential for identifying the risk options related to the Neospora infection in humans. In addition, the figure of the Neospora infection and its complications must be properly identified during pregnancy. The findings may contribute to the implementation of diagnostic tests in routine prenatal screening, especially in people with impaired immune systems. The results of this research can be used as the baseline information for designing and expanding future studies. Therefore, further research using molecular biology tools should be conducted to detect the genomic DNA of Neospora, as well as the genotypic diversity of the isolates.

Acknowledgments

This is a part of the neosporosis project. We greatly appreciate the Dean of the Iranian Veterinary Organization, Hamedan for helping in performing research and providing laboratory materials. This research received no specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Ethical Approval

Not applicable.

Conflict of Interests

The authors declare that they have no competing interests.

References

1. Dubey JP. Review of Neospora caninum and neosporosis in animals. Korean J Parasitol 2003; 41(1):1-16. doi: 10.3347/kjp.2003.41.1.1 [Crossref] [ Google Scholar]
2. Bjerkås I, Mohn SF, Presthus J. Unidentified cyst-forming sporozoon causing encephalomyelitis and myositis in dogs. Z Parasitenkd 1984; 70(2):271-4. doi: 10.1007/bf00942230 [Crossref] [ Google Scholar]
3. Dubey JP, Schares G. Neosporosis in animals--the last five years. Vet Parasitol 2011; 180(1-2):90-108. doi: 10.1016/j.vetpar.2011.05.031 [Crossref] [ Google Scholar]
4. Dubey JP, Schares G, Ortega-Mora LM. Epidemiology and control of neosporosis and Neospora caninum. Clin Microbiol Rev 2007; 20(2):323-67. doi: 10.1128/cmr.00031-06 [Crossref] [ Google Scholar]
5. Dubey JP, Knickman E, Greene CE. Neonatal Neospora caninum infections in dogs. Acta Parasitol 2005; 50(2):176-9. [ Google Scholar]
6. Santos T, Simões R, Mateus T, Lopes A. Updates on Neospora caninum–economical impact. Exp Pathol Health Sci 2016; 8(1):49-50. [ Google Scholar]
7. Namavari MM. Neosporosis in Iran; recent evidences and perspectives. J Zoonotic Dis 2020; 4(2):1-24. doi: 10.22034/jzd.2020.10722 [Crossref] [ Google Scholar]
8. Petersen E, Lebech M, Jensen L, Lind P, Rask M, Bagger P. Neospora caninum infection and repeated abortions in humans. Emerg Infect Dis 1999; 5(2):278-80. doi: 10.3201/eid0502.990215 [Crossref] [ Google Scholar]
9. Duarte PO, Oshiro LM, Zimmermann NP, Csordas BG, Dourado DM, Barros JC. Serological and molecular detection of Neospora caninum and Toxoplasma gondii in human umbilical cord blood and placental tissue samples. Sci Rep 2020; 10(1):9043. doi: 10.1038/s41598-020-65991-1 [Crossref] [ Google Scholar]
10. Lobato J, Silva DA, Mineo TW, Amaral JD, Segundo GR, Costa-Cruz JM. Detection of immunoglobulin G antibodies to Neospora caninum in humans: high seropositivity rates in patients who are infected by human immunodeficiency virus or have neurological disorders. Clin Vaccine Immunol 2006; 13(1):84-9. doi: 10.1128/cvi.13.1.84-89.2006 [Crossref] [ Google Scholar]
11. Barr BC, Conrad PA, Sverlow KW, Tarantal AF, Hendrickx AG. Experimental fetal and transplacental Neospora infection in the nonhuman primate. Lab Invest 1994; 71(2):236-42. [ Google Scholar]
12. McCann CM, Vyse AJ, Salmon RL, Thomas D, Williams DJ, McGarry JW. Lack of serologic evidence of Neospora caninum in humans, England. Emerg Infect Dis 2008; 14(6):978-80. doi: 10.3201/eid1406.071128 [Crossref] [ Google Scholar]
13. Nam HW, Kang SW, Choi WY. Antibody reaction of human anti-Toxoplasma gondii positive and negative sera with Neospora caninum antigens. Korean J Parasitol 1998; 36(4):269-75. doi: 10.3347/kjp.1998.36.4.269 [Crossref] [ Google Scholar]
14. Graham DA, Calvert V, Whyte M, Marks J. Absence of serological evidence for human Neospora caninum infection. Vet Rec 1999; 144(24):672-3. doi: 10.1136/vr.144.24.672 [Crossref] [ Google Scholar]
15. Tranas J, Heinzen RA, Weiss LM, McAllister MM. Serological evidence of human infection with the protozoan Neospora caninum. Clin Diagn Lab Immunol 1999; 6(5):765-7. doi: 10.1128/cdli.6.5.765-767.1999 [Crossref] [ Google Scholar]
16. Benetti AH, Schein FB, dos Santos TR, Toniollo GH, da Costa AJ, Mineo JR. [Inquiry of antibodies anti-Neospora caninum in dairy cattle, dogs and rural workers of the south-west region of Mato Grosso State]. Rev Bras Parasitol Vet 2009; 18 Suppl 1:29-33. doi: 10.4322/rbpv.018e1005.[Portuguese] [Crossref] [ Google Scholar]
17. Oshiro LM, Motta-Castro AR, Freitas SZ, Cunha RC, Dittrich RL, Meirelles AC. Neospora caninum and Toxoplasma gondii serodiagnosis in human immunodeficiency virus carriers. Rev Soc Bras Med Trop 2015; 48(5):568-72. doi: 10.1590/0037-8682-0151-2015 [Crossref] [ Google Scholar]
18. Trees AJ, Williams DJL. Neosporosis in the United Kingdom. Int J Parasitol 2000; 30:891-3. [ Google Scholar]
19. Ibrahim HM, Huang P, Salem TA, Talaat RM, Nasr MI, Xuan X. Short report: prevalence of Neospora caninum and Toxoplasma gondii antibodies in northern Egypt. Am J Trop Med Hyg 2009; 80(2):263-7. [ Google Scholar]
20. Robert-Gangneux F, Klein F. Serologic screening for Neospora caninum, France. Emerg Infect Dis 2009; 15(6):987-9. doi: 10.3201/eid1506.081414 [Crossref] [ Google Scholar]
21. Calero-Bernal R, Horcajo P, Hernández M, Ortega-Mora LM, Fuentes I. Absence of Neospora caninum DNA in human clinical samples, Spain. Emerg Infect Dis 2019; 25(6):1226-7. doi: 10.3201/eid2506.181431 [Crossref] [ Google Scholar]
22. Pal MA. Importance of zoonoses in public health. Indian J Anim Sci 2005; 75(5):586-91. [ Google Scholar]
23. Alemayehu T. Medicinal plants as anti Neospora caninum activity: a systematic review. Int J Vet Sci Technol 2020; 4(2):53-6. [ Google Scholar]
24. Gharekhani J, Yakhchali M, Berahmat R. Neospora caninum infection in Iran (2004-2020): a review. J Parasit Dis 2020; 44(4):1-16. doi: 10.1007/s12639-020-01266-w [Crossref] [ Google Scholar]
25. Carvalho JV, Alves CM, Cardoso MR, Mota CM, Barbosa BF, Ferro EA. Differential susceptibility of human trophoblastic (BeWo) and uterine cervical (HeLa) cells to Neospora caninum infection. Int J Parasitol 2010; 40(14):1629-37. doi: 10.1016/j.ijpara.2010.06.010 [Crossref] [ Google Scholar]
26. Anvari D, Saberi R, Sharif M, Sarvi S, Hosseini SA, Moosazadeh M. Seroprevalence of Neospora caninum infection in dog population worldwide: a systematic review and meta-analysis. Acta Parasitol 2020; 65(2):273-90. doi: 10.2478/s11686-019-00163-4 [Crossref] [ Google Scholar]
27. Ribeiro CM, Soares IR, Mendes RG, de Santis Bastos PA, Katagiri S, Zavilenski RB. Meta-analysis of the prevalence and risk factors associated with bovine neosporosis. Trop Anim Health Prod 2019; 51(7):1783-800. doi: 10.1007/s11250-019-01929-8 [Crossref] [ Google Scholar]
28. Reichel MP, McAllister MM, Nasir A, Moore DP. A review of Neospora caninum in water buffalo (Bubalus bubalis). Vet Parasitol 2015; 212(3-4):75-9. doi: 10.1016/j.vetpar.2015.08.008 [Crossref] [ Google Scholar]
29. Javanmardi E, Majidiani H, Shariatzadeh SA, Anvari D, Shamsinia S, Ghasemi E. Global seroprevalence of Neospora spp in horses and donkeys: a systematic review and meta-analysis. Vet Parasitol 2020; 288:109299. doi: 10.1016/j.vetpar.2020.109299 [Crossref] [ Google Scholar]