Ticks are responsible for the transmission of pathogens of veterinary importance, including those affecting sheep. The current study was designed to investigate co-infections with tick-borne and other pathogens in a naturally infected sheep flock with poor health condition using serology and PCR. Infection with Anaplasma ovis was detected by serology and PCR in 56% of the animals. The presence of Rickettsia spp. of the Spotted Fever Group (SFG) was detected by PCR and sequence analysis in 31% of the animals. All the animals were negative for Anaplasma phagocytophilum either by serology or PCR. Twelve sheep were randomly selected for anatomopathological studies. Five of these animals presented lesions consistent with Mycobacterium tuberculosis complex (MTBC) infection and spoligotyping confirmed infection with Mycobacterium bovis spoligotype SB0339. Co-infection with tick-borne pathogens and MTBC could contribute to the poor health condition observed in these animals but other uncontrolled factors may also be responsible. The differential expression of immune response genes supported previous findings in ruminants and suggested that infection with tick-borne pathogens and M. bovis may results in unique gene expression patterns in sheep. The results underline the need for further research into the possible role of sheep in the epidemiology of animal tuberculosis.