Trypanosomes are the hemoflagellate kinetoplastid protozoan parasites affecting a wide range of vertebrate hosts having insufficient host specificity. Climatic change, deforestation, globalization, trade agreements, close association and genetic selection in links with environmental, vector, reservoir and potential susceptible hosts' parameters have led to emergence of atypical human trypanosomosis (a-HT). Poor recording of such neglected tropical disease, low awareness in health professions and farming community has approached a serious intimidation for mankind. Reports of animal Trypanosoma species are now gradually increasing in humans, and lack of any compiled literature has diluted the issue. In the present review, global reports of livestock and rodent trypanosomes reported from human beings are assembled and discrepancies with the available literature are discussed along with morphological features of Trypanosoma species. We have described 21 human cases from the published information. Majority of cases 10 (47%) are due to T. lewisi, followed by 5 (24%) cases of T. evansi, 4 (19%) cases of T. brucei and 1 (5%) case each of T. vivax and T. congolense. Indian subcontinent witnessed 13 cases of a-HT, of which 9 cases are reported from India, which includes 7 cases of T. lewisi and 2 cases of T. evansi. Apart from, a-HT case reports, epidemiological investigation and treatment aspects are also discussed. An attempt has been made to provide an overview of the current situation of atypical human trypanosomosis caused by salivarian animal Trypanosoma globally.The probable role of Trypanosoma lytic factors (TLF) present in normal human serum (NHS) in providing innate immunity against salivarian animal Trypanosoma species and the existing paradox in medical science after the finding on intact functional apolipoprotein L1 (ApoL1) in Vietnam T. evansi Type A case is also discussed to provide an update on all aspects of a-HT. Insufficient data and poor reporting in Asian and African countries are the major hurdle resulting in under-reporting of a-HT, which is a potential emerging threat. Therefore, concerted efforts must be directed to address attentiveness, preparedness and regular surveillance in suspected areas with training of field technicians, medical health professionals and veterinarians. Enhancing a one health approach is specifically important in case of trypanosomosis.

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