Ureaplasma urealyticum Causes Hyperammonemia in an Experimental Immunocompromised Murine Model

Abstract

Hyperammonemia syndrome is an often fatal complication of lung transplantation which has been recently associated with Ureaplasma infection. It has not been definitely established that Ureaplasma species can cause hyperammonemia. We established a novel immunocompromised murine model of Ureaplasma urealyticum infection and used it to confirm that U. urealyticum can cause hyperammonemia. Male C3H mice were pharmacologically immunosuppressed with mycophenolate mofetil, tacrolimus and oral prednisone for seven days, and then challenged intratracheally (IT) and/or intraperitoneally (IP) with 107 CFU U. urealyticum over six days, while continuing immunosuppression. Spent U. urealyticum-free U9 broth was used as a negative control, with uninfected immunocompetent mice, uninfected immunosuppressed mice, and infected immunocompetent mice serving as additional controls. Plasma ammonia concentrations were compared using Wilcoxon ranks sum tests. Plasma ammonia concentrations of immunosuppressed mice challenged IT/IP with spent U9 broth (n = 14) (range 155–330 μmol/L) were similar to those of normal mice (n = 5), uninfected immunosuppressed mice (n = 5), and U. urealyticum IT/IP challenged immunocompetent mice (n = 5) [range 99–340 μmol/L, p = 0.60]. However, immunosuppressed mice challenged with U. urealyticum IT/IP (n = 20) or IP (n = 15) had higher plasma ammonia concentrations (range 225–945 μmol/L and 276–687 μmol/L, respectively) than those challenged IT/IP with spent U9 broth (p<0.001). U. urealyticum administered IT/IP or IP causes hyperammonemia in mice pharmacologically immunosuppressed with a regimen similar to that administered to lung transplant recipients.

Ureaplasma parvum causes hyperammonemia in a pharmacologically immunocompromised murine model

“…Similar with results of our previous study with U. urealyticum [8], none of the mice not receiving pharmacologic immunosuppression challenged IT/IP with U. parvum developed elevated plasma ammonia concentrations, while immunosuppressed mice challenged with U. parvum IT/IP or IP had higher plasma ammonia levels (up to 1,000 μmol/L) than vehicle-challenged controls (p<0.001). Additionally, in this study, we were able to measure plasma ammonia concentrations of a few mice that died just before the experimental endpoint and found ammonia concentrations up to 1,000 μmol/L or greater.…”

“…Recently, we established an immunocompromised experimental mouse model in which we showed that U. urealyticum ATCC 27618 can cause hyperammonemia [8]. Here, we show that a clinical U. parvum isolate can cause hyperammonemia using the same model.…”

“…Using specialized culture and a Ureaplasma parvum/urealyticum nucleic acid amplification test [7], we recently described a relationship between Ureaplasma infection and hyperammonemia in lung transplant recipients [4]. Based on this finding, we administered an immunosuppression regimen mimicking that administered to lung transplant recipients to laboratory mice, and showed that they developed hyperammonemia when challenged with a type strain of U. urealyticum [8]. In this study, we showed that the related organism, U. parvum , can also cause hyperammonemia in pharmacologically immunosuppressed mice.…”

Successful treatment of Ureaplasma‐induced hyperammonemia syndrome post‐lung transplant

“…Pharmacologically immunosuppressed mice challenged intratracheally (IT) or intraperitoneally (IP) with U. urealyticum were found to have significantly higher plasma ammonia concentrations then those challenged with a negative vehicle‐control. Interestingly, U. urealyticum IT/IP challenged immunocompetent mice did not develop hyperammonemia . A follow up study using U. parvum found similar results, with hyperammonemia only seen in immunosuppressed mice, not immunocompetent mice, challenged with U. parvum IT/IP .…”

“…Additionally, two prospective patients identified with hyperammonemia syndrome and U. parvum infection responded to antimicrobial treatment . Subsequently, a murine model was used to confirm that U. urealyticum and U. parvum infection could cause elevated plasma ammonia concentrations in pharmacologically immunocompromised mice …”