Mannheimia haemolytica (previously known as Pasteurella haemolytica) is a weakly hemolytic, gram-negative
coccobacillus that is an opportunistic pathogen of cattle, sheep and other ruminants. Pasteurellosis kills at least one
percent of North American feedlot cattle and is responsible for morbidity, decreased weight gain and loss of
performance in at least an additional ten percent of these animals. Consequently, the disease costs the United States
cattle industry nearly a billion dollars annually. It is also a common disease of sheep, where outbreaks are also
associated with management practices such as overcrowding and transport. M. haemolytica is also a prevalent cause
of ovine mastitis in the United Kingdom. In addition, it can cause disease other ruminants, including goats, bison, and
bighorn sheep.

Mannheimia haemolytica is a member of the gamma subdivision of the Proteobacteria in the family Pasteurelleaceae,
commonly called the
Haemophilus, Actinobacillus, and Pasteurella (HAP) family. Haemophilus ducreyii is most closely
related to M. haemolytica based on 16S rRNA sequences. Eleven serotypes (1, 2, 5, 6, 7, 8, 9, 12, 13, 14, and 16),
originally known as biotype A, are included in the species. Worldwide, ST1 and ST2 are the most prevalent serotypes
found: ST1 is recognized as the most common cause of pasteurellosis in cattle, but other serotypes are occasionally
associated with disease; ST2 causes disease in sheep, but it is also a predominant member of the upper respiratory
tract (URT) flora of healthy calves. The strain being sequenced, strain PHL213, is an ST1 strain isolated from the lung
of a pneumonic calf.

Mannheimia (Pasteurella) haemolytica A1 is the primary bacterial agent of bovine pneumonic pasteurellosis (shipping
fever), which is characterized by acute lobar fibronecrotizing pneumonia with extensive peripheral blood neutrophil
(PMN) infiltration in small airways and alveoli (4, 39, 47).

1: Infect Immun. 2008 Nov;76(11):5357-65. Epub 2008 Sep 2.
Atapattu DN, Albrecht RM, McClenahan DJ, Czuprynski CJ.
Department of Pathobiological Sciences, 2015 Linden Drive West, University of Wisconsin-Madison, Madison, WI
53706, USA.

Exotoxins which belong to the family containing the RTX toxins (repeats in toxin) contribute to a variety of important
human and animal diseases. One example of such a toxin is the potent leukotoxin (LKT) produced by the bovine
respiratory pathogen Mannheimia haemolytica. LKT binds to CD18, resulting in the death of bovine leukocytes. In this
study, we showed that internalized LKT binds to the outer mitochondrial membrane, which results in the release of
cytochrome c and collapse of the mitochondrial membrane potential (psi(m)). Incubation of bovine lymphoblastoid cells
(BL-3 cells) with the mitochondrial membrane-stabilizing agent cyclosporine (CSA) reduced LKT-mediated cytotoxicity,
cytochrome c release, and collapse of the psi(m). Coimmunoprecipitation and intracellular binding studies suggested
that LKT binds to the mitochondrial matrix protein cyclophilin D. We also demonstrated that LKT mobilizes the vesicle
scission protein dynamin-2 from mitochondria to the cell membrane. Incubation with CSA depleted mitochondrial
dynamin-2 in BL-3 cells, making it unavailable for vesicle scission and LKT internalization. The results of this study
show that LKT trafficking and LKT-mediated cell death involve dynamin-2 and cyclophilin D, in a process that can be
prevented by the mitochondrial membrane-protecting function of CSA.