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During the last twenty years, zoonotic visceral leishmaniasis (ZVL) spread from the north characterized by humid, sub-humid, and semi-arid bio-climates to the arid areas located in Central Tunisia. In order to understand the eco-epidemiological factors involved in the distribution of ZVL, both a sero-epidemiological and an entomological investigation were performed in two governorates situated in two different bio-geographical areas: Bizerte in the north and Kairouan in the center. A mathematical model for transmission of ZVL was built, describing the disease dynamic in these areas. Among 108 sera collected from clinically healthy owned dogs used for guarding houses in the governorate of Bizerte and tested for anti-L. infantum antibodies by indirect immune-fluorescence antibody test (IFAT), 8.3% were positive. From a total of 191 serum samples collected from clinically healthy owned dogs used for guarding houses in the governorate of Kairouan and tested for anti-L. infantum antibodies by IFAT, 26.7% were sero-positive. The cumulative incidences of ZVL in humans in the governorates of Bizerte and Kairouan were 39.17/100,000 and 0.2/100,000 inhabitants, respectively. The infection rates of sand flies with Leishmania DNA in the governorate of Bizerte and Kairouan were 3.8% and 9.4%, respectively. It is important to point out that ZVL epidemic in humans is preceded or concomitant to a high prevalence of Leishmania infantum in dogs and in sand flies. The model showed also a non-linear relationship between dog infection and ZVL in humans. These results suggest an important force of infection (RO) in emerging foci such as the governorate of Kairouan leading to an increased incidence of ZCL in humans. A high prevalence of L.infantum in dogs will result in high prevalence in the vector and obviously high probability to infect human; that it is a key factor for triggering transmission to humans, and subsequently it is an important parameter in the control of ZVL transmission.