Characterization of lethal inhalational infection with Francisella tularensis in the common marmoset (Callithrix jacchus)

Abstract

The intracellular Gram-negative pathogen Francisella tularensis is the causative agent of tularaemia and is prevalent in many countries in the northern hemisphere. To determine whether the common marmoset (Callithrix jacchus) would be a suitable non-human primate model of inhalational tularaemia, a pathophysiology study was undertaken. Ten animals were challenged with ∼102 c.f.u. F. tularensis strain SCHU S4 (F. tularensis subsp. tularensis). To look for trends in the infection, pairs of animals were sacrificed at 24 h intervals between 0 and 96 h post-challenge and blood and organs were assessed for bacteriology, pathology and haematological and immunological parameters. The first indication of infection was a raised core temperature at 3 days post-challenge. This coincided with a number of other factors: a rapid increase in the number of bacteria isolated from all organs, more pronounced gross pathology and histopathology, and an increase in the immunological response. As the disease progressed, higher bacterial and cytokine levels were detected. More extensive pathology was observed, with multifocal lesions seen in the lungs, liver and spleen. Disease progression in the common marmoset appears to be consistent with human clinical and pathological features of tularaemia, indicating that this may be a suitable animal model for the investigation of novel medical interventions such as vaccines or therapeutics.

Bioavailability and Efficacy of Levofloxacin against Francisella tularensis in the Common Marmoset ( Callithrix jacchus )

“…This may, at least in part, be related to the higher dose used in the marmoset studies (2,3,12,15). In the current study, the time to death, activity, temperature profile, and bacterial load at postmortem in the nontreated animals were consistent with previously reported data (21). Clinical parameters were investigated in the current study and showed a statistically significant decrease in the platelet counts and an increase in the alkaline phosphatase levels, as well as notable changes in the levels of potassium, ALT, and glucose from the baseline.…”

“…However, in order to undertake the pivotal studies required for the licensure of any therapy, nonhuman primate models of infection are required. Previous work has demonstrated that the common marmoset (Callithrix jacchus) is susceptible to experimental inhalational tularemia and develops a lethal infection representative of human disease (21).…”

“…Marmosets were anesthetized with 25 mg kg Ϫ1 ketamine administered intramuscularly prior to exposure and challenged in pairs by the airborne route (18,21). Briefly, a Collison nebulizer containing 20 ml F. tularensis and 3 drops of Antifoam 289 (Sigma) was used to generate aerosol particles of approximately 1 to 3 m. The aerosol was conditioned in a modified Henderson apparatus (7).…”

Differential Virulence and Disease Progression following Mycobacterium tuberculosis Complex Infection of the Common Marmoset (Callithrix jacchus)

“…These are large, outbred animals, however, which limits the number of animals that can be studied, and they require large doses of prospective antibiotics, which limits the number of agents available to study. We therefore decided to explore the smaller New World primates and identified the common marmoset as a potential model for TB chemotherapy due to its small size (250 to 400 g as an adult), ease of husbandry, wide use in other disease models (10)(11)(12)(13)(14), and high incidence of dizygotic twinning (15). There was only a single case report of a zoonotic infection in the published literature involving a marmoset companion animal infected by a human in South Africa (16).…”

Animal Models forFrancisella tularensisandBurkholderiaSpecies

“…68 Primates also develop skin ulcers and lymphadenopathy characteristic of human disease, whereas small animal models do not. 66 For these and other reasons, small animals are more suitable for proof-of-concept studies or to generate supportive data. Pivotal studies for approval of MCMs against tularemia under the Animal Rule will likely involve the use of NHPs.…”