Hereditary Hemochromatosis Restores the Virulence of Plague Vaccine Strains

Abstract

Nonpigmented Yersinia pestis (pgm) strains are defective in scavenging host iron and have been used in live-attenuated vaccines to combat plague epidemics. Recently, a Y. pestis pgm strain was isolated from a researcher with hereditary hemochromatosis who died from laboratory-acquired plague. We used hemojuvelin-knockout (Hjv(-/-)) mice to examine whether iron-storage disease restores the virulence defects of nonpigmented Y. pestis. Unlike wild-type mice, Hjv(-/-) mice developed lethal plague when challenged with Y. pestis pgm strains. Immunization of Hjv(-/-) mice with a subunit vaccine that blocks Y. pestis type III secretion generated protection against plague. Thus, individuals with hereditary hemochromatosis may be protected with subunit vaccines but should not be exposed to live-attenuated plague vaccines.

Intramuscular Immunization of Mice with a Live-Attenuated Triple Mutant of Yersinia pestis CO92 Induces Robust Humoral and Cell-Mediated Immunity To Completely Protect Animals against Pneumonic Plague

“…However, these EV76-based vaccines are not genetically uniform and are also highly reactogenic (14); hence, they do not meet the standards for FDA approval. In addition, the ⌬pgm mutants of Y. pestis (e.g., the KIM/D27 strain) may not be safe because of a reported case of fatal infection in an individual with hemochromatosis (15,16).In an effort to search for a new live-attenuated plague vaccine, we recently constructed a ⌬lpp ⌬msbB ⌬ail triple mutant, with deleted genes encoding Braun lipoprotein (Lpp), an acetyltransferase (MsbB), and the attachment invasion locus (Ail) (17). Lpp …”

“…However, these EV76-based vaccines are not genetically uniform and are also highly reactogenic (14); hence, they do not meet the standards for FDA approval. In addition, the ⌬pgm mutants of Y. pestis (e.g., the KIM/D27 strain) may not be safe because of a reported case of fatal infection in an individual with hemochromatosis (15,16).…”

Assessment of Potential Long Term Health Effects on Army Human Test Subjects of Relevant Biological and Chemical Agents, Drugs, Medications and Substances

“…A study of 208 Kurdish patients exposed to high doses of mus-33 tard gas in 1987 looked at spirometric function and angiotensin-converting enzyme (ACE) genotyping 18 years after exposure. 122 This study found that FEV1 % predicted tended to be higher in association with the D allele. Specifically, the FEV1 % predicted was 68.03 ± 20.5%, 69.4 ± 21.4% and 74.8 ± 20.1% for II, ID, and DD genotypes respectively.…”

“…123 The small number of reported lung cancers after single high-dose exposures are too few to determine whether the cancers were due to mustard gas exposure or whether they were caused by confounding factors such as smoking or other environmental exposures. 122 On the other hand, a small study of 20 lung-cancer patients with single high-dose mustard exposures found a lower than expected age at onset (< 40 years of age) of lung cancer for seven of the patients. 124 Additionally, p53 mutations (within exons 5-8) were predominately G to A transitions; a mutation consistent with the DNA lesion caused by mustard gas.…”

Plague Gives Surprises in the First Decade of the 21st Century in the United States and Worldwide

“…32,33 Support for this mechanism was provided by experiments in a genetically defined strain of mice that mimics human hemochromatosis, showing that the nonpigmented Y. pestis in this case exhibited greater lethality in mice with hemochromatosis than in normal mice. 35 Both of these scientists sought medical care for their symptoms but neither told doctors about suspected exposures, leading to missed diagnoses and omission of needed antibiotic treatment. Our lessons should be a reminder that handling dead animals in a plague-endemic area is dangerous and that avirulent mutants of Y. pestis can unexpectedly cause disease in immunocompromised persons, specifically those with hemochromatosis and diabetes mellitus, who do not adhere to laboratory safety precautions.…”