Brucella are adept at inhibiting the host immune response. Brucella virulence derives from expression of an LPS with reduced agonist activity that limits activation of innate immunity and development of an effective adaptive response that promotes invasion and establishment of a replicative niche. In addition, Brucella express a protein TcpB (or Btp1) that restricts the proinflammatory response by interfering with MyD88 function. The result is enhanced degradation of MAL (MyD88-adapter-like protein) and restricted expression of NFκB. However, our current results indicate infection varies in different tissues, and that this variation is attributable in part to various PRRs, including TLR2, TLR4, and downstream signaling partners, like MyD88. Interference with TLR signaling by the organism has been described in numerous studies, as has the prominent contribution of MyD88 in limiting infection. The results reported here confirm the importance of MyD88 in the control of infection and extend those findings to include three tissues; spleen, liver and lung. In addition, the experiments performed confirm previous findings concerning the lack of significant contribution of TLR4 and TLR2 with regard to spleen (and liver) infection, but reveal their significant contribution preventing lung infection.