eNews January 11, 2012

Borrelia hermsii-infected, humanized NSG mice: a better model of relapsing fever

The humanized NSG mouse is proving to be an immensely powerful platform for studying human diseases in a near-human context. In 2011, a research team led by Drs. Tim Manser and Kishore Alugupalli from the Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University (TJU), Philadelphia, demonstrated the utility of this mouse as a model of human relapsing fever (Vuyyuru et al. 2011). Further studies of relapsing fever using this mouse should lead to improved therapies for this and similar infectious diseases.

Relapsing fever

Relapsing fever is an infectious disease caused by spirochete bacteria of the genus Borrelia. Generally, it is transmitted through the bites of rodent-inhabiting lice or soft-bodied ticks. The more common variety is tick-borne and is caused by B. hermsii. It occurs primarily in Africa, Spain, Saudi Arabia, Asia and western parts of the U.S. and Canada. Most B. hermsii-infected people get sick 5-15 days after being bitten. The symptoms may include a sudden fever, chills, headaches, muscle or joint aches, nausea and a rash. They continue for 2-9 days, disappear, and then recur. If the infection is not treated, this cycle may continue for several weeks (hence, the name relapsing fever). Seldom involving complications and rarely fatal, relapsing fever is easily treated with antibiotics.

Humanized NSG mice are excellent for modeling relapsing fever

Although rodent models have taught us a great deal about the pathogenesis of infectious diseases, they aren't people. As a result, it is quite common that what we learn from rodents isn't completely applicable to humans. Therefore, to understand the pathogenesis and immune responses to B. hermsii in as human a context as possible, the TJU researchers studied them in infected humanized NSG mice, NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (005557). To produce these mice, the researchers populated NSG mice with hematopoietic stem cells (HSCs) derived from fetal human cord blood. They dubbed the mice "human immune system mice" (HISmice, which are the same as our CD34+ humanized NSG mice) because some of the engrafted HSCs differentiate and develop into all the cell types of human myeloid and lymphoid lineages. The TJU researchers found that B. hermsii-infected humanized NSG mice are excellent models of human relapsing fever:

  • In contrast to infected NSG and other B cell-deficient mice, which exhibit persistent bacteremia, infected humanized NSG mice exhibit recurrent episodes of bacteremia, the hallmark of human relapsing fever.
  • They develop splenomegaly, a characteristic of other B. hermsii-infected mice and humans.
  • As do humans, B. hermsii-infected- humanized NSG mice resolve the bacteremial episodes in a B cell-dependent but T cell-independent fashion.
  • They resolve the primary bacteremia episode by generating B. hermsii-specific human IgM.
  • Similar to B. hermsii-infected humans and mice, infected, humanized NSG mice generate antibody responses to the B. hermsii outer-membrane protein Factor H binding protein A (FhbA).
  • The infected, humanized NSG mice develop a population of  CD20+CD27+CD43+CD70 B cells, a proposed human equivalent to the B1b cells other infected mice use to mount an anti-B. hermsii response (neutralizing this subset lessens the anti-B.hermsii response by infected, humanized NSG mice).
  • The frequency of human B1 cells differentiated from human umbilical cord blood HSCs and the overall B cell composition of B. hermsii-infected, humanized NSG mice are very similar to those in human umbilical cord blood.
B. hermsii-infected humanized NSG mice (HISmice) appear to be excellent models of human relapsing fever.

The TJU team found that though infected, humanized NSG mice control B. hermsii infection, they do so less efficiently than do wild-type C57BL/6J (B6J, 000664) mice. They also have a more difficult time controlling the highly virulent DAH-p1 than the less virulent DAH-p19 B. hermsii strain. The reasons for these findings are unclear but suggest that the immune responses generated by the human fetal cord blood-derived B cells in the infected, humanized NSG mice are suboptimal.

In summary, the TJU team's findings suggest that B. hermsii-infected humanized NSG mice are an excellent model for studying the pathogenesis of, and immune responses to, human relapsing fever. Further studies should identify not only which of the B-cell populations in these mice are the key immune responders but why these mice clear B.hermsii infections less efficiently than B6J mice. They should also help improve therapies for relapsing fever and similar infectious diseases.