Immunotherapy for tularemia

Abstract

Francisella tularensis is a gram-negative bacterium that causes the zoonotic disease tularemia. Francisella is highly infectious via the respiratory route (~10 CFUs) and pulmonary infections due to type A strains of F. tularensis are highly lethal in untreated patients (>30%). In addition, no vaccines are licensed to prevent tularemia in humans. Due to the high infectivity and mortality of pulmonary tularemia, F. tularensis has been weaponized, including via the introduction of antibiotic resistance, by several countries. Because of the lack of efficacious vaccines, and concerns about F. tularensis acquiring resistance to antibiotics via natural or illicit means, augmentation of host immunity, and humoral immunotherapy have been investigated as countermeasures against tularemia. This manuscript will review advances made and challenges in the field of immunotherapy against tularemia.

Hematopoietic MyD88 and IL-18 are essential for IFN-γ–dependent restriction of type A Francisella tularensis infection

“…Although TLR2, which must have MyD88 for signaling [62], is critical for protection against LVS and F. novicida [22], lipids derived from type A F. tularensis, but not LVS or F. novicida, actually suppress host immune responses via TLR2 [12,27]. In addition, MyD88-dependent TLR agonists confer much more efficacious protection against F. novicida and LVS than against type A F. tularensis [5]. Thus, TLR signaling may be more critical to the protective role of MyD88 in response to LVS or F. novicida, than to protection against type A F. tularensis.…”

“…For intratracheal infection, mice were anesthetized with isoflurane, and a 22-gauge blunted needle was passed through the oral pharynx into the trachea. A 50 ml volume of PBS containing 75 CFU of SchuS4 then was injected into the lung [5]. In some experiments IFN-g was depleted in vivo via i.p.…”

“…In addition, lymphadenopathy and ulcers may persist for months, even with appropriate antibiotic therapy [2,4]. Data from experimental models suggest that a more robust immune response to cutaneous rather than pulmonary Francisella infection in part explain the differential host susceptibility to infection by these routes [5,6]. Despite this differential susceptibility to infection, in mice it has been shown that the control of systemic, rather than pulmonary, bacterial burden is critical to surviving challenge with type A F. tularensis, regardless of the route of infection [7,8].…”

“…These strains have been extensively studied as model intracellular pathogens [10,11]. However, type A strains of F. tularensis possess immune evasion capabilities not observed in model Francisella strains [5,[12][13][14], and numerous vaccines and immunotherapeutics that confer potent protection against model strains of Francisella have demonstrated little or no efficacy against challenge with type A F. tularensis [5,11,[15][16][17]. Therefore, results of studies investigating elicited and protective immune responses against model strains of Francisella are not always applicable to strains of Francisella that cause disease in humans.…”

Sensitive Detection of Francisella tularensis Directly from Whole Blood by Use of the GeneXpert System

“…rancisella tularensis, the causative agent of tularemia, is classified as a tier 1 select agent by the CDC (1) because of its high infectivity at low doses and its potential for being developed as a bioweapon (2)(3)(4)(5)(6)(7)(8). Tularemia can be easily misdiagnosed due to similarities in clinical presentations with other infectious diseases (9,10).…”