The biomarker is the putative N-acetylmuramoyl-L-alanine amidase RC0497, a protein that was identified through an analysis of human umbilical vein endothelial cells infected with the bacterial pathogen Rickettsia conorrii. A blood test for the protein was successfully tested in a mouse model and in serum samples taken from infected humans, co-lead investigator Yingxin Zhao, PhD, a scientist at the Sealy Center for Molecular Medicine, University of Texas Medical Branch (UTMB), and colleagues reported.
"The detection of RC0497 has the potential to be a sensitive and speciﬁc marker for acute rickettsial spotted rickettsioses," the authors wrote (Am J Pathol, February 2020, Vol. 190:2, pp. 306-322).
Mediterranean spotted fever and other rickettsial infections are difficult to diagnose and can be fatal in 20% to 60% of cases if they are not treated, according to the U.S. Centers for Disease Control and Prevention (CDC). Symptoms include a dry and dark scab, fever, headache, and rash.
"The epidemiology of the spotted fever group infections is muddled by misdiagnosis, underdiagnosis, and underreporting," Zhao and colleagues wrote.
The group plans to conduct additional research to bolster the results and foresees the development of a point-of-care diagnostic for spotted fever infections.
High unmet need
R. conorii is one of the most virulent strains of the Gram-negative genus Rickettsia, the authors noted. As one could assume by its name, Mediterranean spotted fever is prevalent in the Mediterranean basin, and it is also reported in Africa, the Middle East, and India. The study just reported in the American Journal of Pathology was conducted in light of a high unmet need for the diagnosis of rickettsial infections. Indirect immunofluorescence antibody testing may be conducted two to four weeks after the illness strikes. Many cases are misdiagnosed at the beginning.
"Because there are no available tests of early infection, Mediterranean spotted fever is often undiagnosed and untreated, resulting in signiﬁcant mortality," the authors wrote.
The study was supported by grants to the researchers from the U.S. National Institutes of Health (NIH), as well as from the UTMB's Sealy Center for Molecular Medicine and Institute for Translational Sciences. Zhao and three other study co-authors have applied for methods and composition patents for the diagnosis of Rickettsia infection. It involved testing with what the researchers describe as a highly sensitive mass spectometry assay.
The analysis of umbilical vein endothelial cells showed that 104 proteins were more abundant in the presence of acute R. conorrii infections, and of these, one -- RC0497 -- was a rickettsial protein, the authors reported.
The researchers tested for the protein in samples from 13 infected people, including those with acute illness and convalescence, and compared the results with six healthy controls. Among the proteins that were secreted during acute illness, the biomarker was the most abundant when cardiovascular infection was present. Circulating RC0497 varied in accordance with the severity of the disease and was present in samples from convalescent patients as well as those with acute illness.
"The level of RO497 was elevated in the serum samples from patients with acute MSF relative to healthy controls," the authors wrote. "However, a cohort of samples taken at different stages of acute infection will be needed to determine how soon after onset RC0497 can be detected in the blood."
The researchers concluded that the biomarker appears to be relevant in other types of spotted fever infections, notably the Rocky Mountain type. The CDC website lists 18 different types of spotted fever infections, including African tick-bite fever and Rocky Mountain spotted fever, the latter of which the agency described as "one of the deadliest [tick-borne] diseases in the Americas."
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