Ureaplasma parvum causes hyperammonemia in a pharmacologically immunocompromised murine model

Abstract

A relationship between hyperammonemia and Ureaplasma infection has been shown in lung transplant recipients. We have demonstrated that Ureaplasma urealyticum cases hyperammonemia in a novel immunocompromised murine model. Herein, we determined whether Ureaplasma parvum can do the same. Male C3H mice were given mycophenolate mofetil, tacrolimus and prednisone for seven days, and then challenged with U. parvum intratracheally (IT) and/or intraperitoneally (IP), while continuing immunosuppression over six days. Plasma ammonia concentrations were determined and compared using Wilcoxon ranks sum tests. Plasma ammonia concentrations of immunosuppressed mice challenged IT/IP with spent broth [median, 188 μmol/L; range, 102–340 μmol/L] were similar to those of normal [median, 226 μmol/L; range, 154–284 μmol/L, p>0.05], uninfected immunosuppressed [median, 231 μmol/L; range, 122–340 μmol/L, p>0.05], and U. parvum IT/IP challenged immunocompetent [median, 226 μmol/L; range, 130–330 μmol/L, p>0.05] mice. Immunosuppressed mice challenged with U. parvum IT/IP (median 343 μmol/L; range 136–1,000 μmol/L) or IP (median 307 μmol/L; range 132–692 μmol/L) had higher plasma ammonia concentrations than those challenged IT/IP with spent broth (p<0.001). U. parvum can cause hyperammonemia in pharmacologically immunocompromised mice.

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

“…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 . As seen in human case reports, the immunocompromised state appears to be important for the development of Ureaplasma ‐induced hyperammonemia.…”

“…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 …”

Successful resolution of hyperammonemia following hematopoietic cell transplantation with directed treatment of Ureaplasma parvum infection

“…Additional reports have indicated that acquired deficiency of hepatic glutamine synthetase or urea cycle disorders may lead to hyperammonemia in transplant recipients [19][20][21] . Ureaplasma Ureaplasma parvum can induce hyperammonemia in immunosuppressed mice 24,25 . Of interest is a recent report implicating Mycoplasma hominis as a cause of hyperammonemia following lung transplantation, which is intrinsically resistant to macrolides but is usually susceptible to fluoroquinolones, as are Ureasplasma spp.…”

Hyperammonemia syndrome due to Ureaplasma infection after liver‐kidney transplant

“…However, the link between HE and Mycoplasma infection was first suggested in 2013, 14 when a lung transplant recipient died from HE and was found to have disseminated infection with M hominis . Subsequently, hyperammonemia syndrome was linked to disseminated Ureaplasma infection in post‐lung transplant patients, 4 and it was demonstrated that by hydrolyzing urea to generate adenosine triphosphate (ATP) U urealyticum and U parvum caused elevated plasma ammonia levels in infected, immunocompromised mice 8 . Interestingly, subsequent analysis of the first patient identified with M hominis infection and hyperammonemia 14 showed that Ureaplasma was also present, raising the question of whether M hominis truly played a role in the development of hyperammonemia or not 4 …”

“…In the past, this syndrome has been difficult to treat, with high mortality rates 3 . It is now understood that bacteria from the genera Ureaplasma are implicated as organisms associated with this syndrome 4,8,9 . However, making this diagnosis after liver transplant is more challenging, as hyperammonemia following liver transplantation has many other causes, including portal vascular abnormalities (especially thrombosis), 10 inborn errors of metabolism, 11 or dysfunction of the liver allograft.…”