400 G.A. Cabral and A. Staab
3.2
In Vivo Infections
Guinea pigs and mice have been used extensively as experimental in vivo models
for documenting the effects of cannabinoids on host resistance. One of the earliest
studies that indicated cannabinoids exacerbated host resistance to microbes was
reported by Bradley et al. (1977), who demonstrated enhanced susceptibility of
mice to combinations of THC and live or killed gram-negative bacteria. Mora-
han et al. (1979) demonstrated that mice exposed to THC were compromised in
their ability to resist infection to viral and bacterial agents. BALB/c mice adminis-
tered THC intraperitoneally exhibited decreased resistance to infection with either
Listeria monocytogenes or HSV-2. Mishkin and Cabral (1985) and Cabral et al.
(1986a,b) confirmed and extended these studies. THC was shown to increase in
a dose-related fashion the susceptibility to HSV-2 genital infection in guinea pigs
and mice. Animals treated with THC exhibited greater severity of herpes genitalis,
higher mortalities, and higher mean titers of virus shed from the vagina. Sup-
pression of antibody production to HSV-2 and a delay in the onset of the delayed
hypersensitivity response to HSV-2 were observed. Cabral et al. (1987b) also noted
that THC caused a reduction of the splenocyte proliferative response to HSV-2.
It was suggested that THC inhibited immune responsiveness of (B 6 C 3 )F 1 mice to
homotypic challenge with HSV-2.
Specter et al. (1991) reported that THC augmented murine retroviral-induced
immunosuppression and infection. It was noted that THC in vitro administration
to spleen cells from mice infected with Friend leukemia virus (FLV) resulted in
a decrease, beyond that seen with virus or THC alone, in lymphocyte blastogen-
esis and NK cell activity. Moreover, when both FLV and THC were administered
to mice concurrently infected with HSV, mortality attributed to FLV infection oc-
curred significantly more rapidly than in the absence of HSV or THC. Paradise
and Friedman (1993), using a hamster model, indicated that THC enhanced in-
fection withT. pallidum, the causative agent of syphilis in humans. A greater
degree of enhancement was exhibited also in rabbits in that treponemes pro-
liferated more readily during treatment with THC than in control animals. In
addition, Marciano-Cabral et al. (2001) reported that THC exacerbated brain in-
fection in mice byAcanthamoeba, free-living amoebae that act as opportunistic
pathogens.
There is accumulating data that alterations in cytokine expression play a crit-
ical role in enhanced mortality and morbidity in experimental animals. Klein
et al. (1993) reported that THC induced cytokine-mediated mortality of mice
infected withL. pneumophila. Mice administered two injections of THC, one
before and one after a sublethal dose ofLegionellaexperienced acute collapse
and death. The THC-induced mortality resembled cytokine-mediated shock, and
acute-phase serum from these animals contained significantly elevated levels of
TNF and IL-6. The investigators concluded that THC increased the blood levels
of acute-phase cytokines in the infected animals and that these elevated levels,
at least in part, accounted for mortalities induced by THC. Newton et al. (1994)
demonstrated that drug treatment of mice suppressed Th 1 anti-Legionellaimmu-