Bayesian compartmental models and associated reproductive numbers for an infection with multiple transmission modes

Zoonotic visceral leishmaniasis (ZVL) is a serious neglected tropical disease that is endemic in 98 countries. ZVL is primarily transmitted via a sand fly vector. In the United States, it is enzootic in some canine populations; it is transmitted from infectious mother to pup transplacentally, and vector-borne transmission is absent. This absence affords a unique opportunity to study (1) vertical transmission dynamics in dogs and (2) the importance of vertical transmission in maintaining an infectious reservoir in the presence of a vector. In this paper, we present Bayesian compartmental models and reproductive number formulations to examine (1) and (2), providing a mechanism to plan and evaluate interventions in regions where both transmission modes are present. First, we propose an individual-level susceptible, infectious, removed (SIR) model to study the effect of maternal infection status during pregnancy on pup infection progression. We provide evidence that pups born to diagnostically positive mothers during pregnancy are more likely to become diagnostically positive both earlier in life, and at some point during their lifetime, than those born to diagnostically negative mothers. Second, we propose a population-level SIR model to study the impact of a vertically maintained reservoir on propagating infection in a naive canine population through emergent vector transmission using simulation studies. We also present reproductive numbers to quantify contributions of vertically infected and vector-infected dogs to maintaining infection in the population. We show that a vertically maintained canine reservoir can propagate infection in a theoretical naive population in the presence of a vector.     

Substrate/Inhibitor Properties of Human Deoxycytidine Kinase (dCK) and Thymidine Kinases (Tk1 And Tk2) Towards the Sugar Moiety of Nucleosides,Including O′-Alkyl Analogues

Abstract

Nucleoside analogues with modified sugar moieties have been examined for their substrate/inhibitor specificities towards highly purified deoxycytidine kinase (dCK) and thymidine kinases (tetrameric high-affinity form of TK1, and TK2) from human leukemic spleen. In particular, the analogues included the mono-and di-O′-methyl derivatives of dC, dU and dA, syntheses of which are described. In general, purine nucleosides with modified sugar rings were feebler substrates than the corresponding cytosine analogues. Sugar-modified analogues of dU were also relatively poor substrates of TK1 and TK2, but were reasonably good inhibitors, with generally lower K_i values vs TK2 than TK1. An excellent discriminator between TK1 and TK2 was 3′-hexanoylamino-2′,3′-dideoxythymidine, with a K_i of ～600 μM for TK1 and ～0.1 μM for TK2. 3′-OMe-dC was a superior inhibitor of dCK to its 5′-O-methyl congener, consistent with possible participation of the oxygen of the (3′)-OH or (3′)-OMe as proton acceptor in hydrogen bonding with the enzyme. Surprisingly α-dT was a good substrate of both TK1 and TK2, with K_i values of 120 and 30 μM for TK1 and TK2, respectively; and a 3′-branched α-L-deoxycytidine analogue proved to be as good a substrate as its α-D-counterpart. Several 5 ′-substituted analogues of dC were