Phenotypes Associated with This Genotype

Genotype
MGI:3577712

• Allelic Composition: Myd88^tm1Aki/Myd88^tm1Aki
• Genetic Background: B6.129P2-Myd88^tm1Aki

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

respiratory system

bronchiolitis ( J:162707 )

• rMA15 SARS-CoV-infected mice show denuding bronchiolitis not seen in wild-type mice

mortality/aging

increased susceptibility to Coronaviridae infection induced morbidity/mortality ( J:162707 )

• rMA15 SARS-CoV-infected mice show greater than 90% mortality by 6 dpi compared to 100% survival in controls

cellular

increased apoptosis ( J:102879 )

• 5 days after lung injury, mutants show significantly increased numbers of apoptotic lung epithelial and inflammatory cells

abnormal dendritic cell differentiation ( J:139001 )

• dendritic cell maturation fails to occur in vivo upon exposure to TLR9 agonists

abnormal neuron differentiation ( J:129957 )

• improved differentiation of progenitor cells into neurons

• survival of newly formed neurons is reduced

homeostasis/metabolism

increased physiological sensitivity to xenobiotic ( J:102879 )

• knockout mice are more susceptible to bleomycin-induced lung injury

decreased susceptibility to kidney reperfusion injury ( J:146120 )

• moderately protected from ischemia reperfusion injury as measured by serum creatinine levels 24 hours after injury

immune system

abnormal dendritic cell differentiation ( J:139001 )

• dendritic cell maturation fails to occur in vivo upon exposure to TLR9 agonists

increased dendritic cell number ( J:116763 )

• increased numbers of dendritic cells in brains of mice infected with Plasmodium

abnormal immune system physiology ( J:121070 )

• response to LPS and CpG is completely abrogated

abnormal T cell physiology ( J:97662 )

• induction of the antigen-specific CD8+ T-cell response by immunizing with soluble ovalbumin and TLR9 agonists, but not TLR2 and TLR6 agonists, was severely impaired

abnormal dendritic cell physiology ( J:116670 , J:118954 )

• cytokine secretion elicited by zymosan or LPS is impaired (J:116670)

• following infection with attenuated yellow fever vaccine 17D (YF-17D), dendritic cells produce less IL-12p40, IL-6 and interferon-gamma relative to wild-type mice (J:118954)

abnormal cytokine secretion ( J:116670 , J:162707 )

• LPS-induced cytokine production by BMDCs is almost abolished compared to controls and Myd88-sufficient mutants (J:116670)

• rMA15 SARS-CoV-infected mice show decreased expression of proinflammatory cytokines and chemokines, showing reduced induction of CCL2, CCL3, and CCL5, TNF-alpha, and IL-1beta (J:162707)

abnormal chemokine secretion ( J:102879 )

• hyaluronan fragment-induced expression of chemokines by peritoneal macrophages is completely abolished in double knockout mice

decreased interferon-alpha secretion ( J:97662 )

• CpG-A or RNA polyuridylic acid induced production of interferon-alpha was abolished in plasmacytoid dendritic cells

decreased interferon-gamma secretion ( J:116763 , J:118954 )

• less up regulation of INF-gamma in Plasmodium infection (J:116763)

• following infection with attenuated yellow fever vaccine 17D (YF-17D), dendritic cells produce less interferon-gamma (J:118954)

decreased interleukin-12 secretion ( J:116670 )

• after stimulation with zymosan, TNF production is significantly reduced in Myd88-deficient animals

decreased interleukin-12b secretion ( J:116763 , J:118954 )

• less upregulation of IL-12b in Plasmodium infection (J:116763)

• following infection with attenuated yellow fever vaccine 17D (YF-17D), dendritic cells produce less IL-12p40 relative to wild-type mice (J:118954)

decreased interleukin-6 secretion ( J:118954 , J:121070 )

• following infection with attenuated yellow fever vaccine 17D (YF-17D), dendritic cells produce less IL-6 relative to wild-type mice (J:118954)

• following treatment with PbA(Plasmodium bergbei ANKA)-parasitized erythrocytes or LPS-stimulation, IL-6 secretion is reduced (J:121070)

decreased tumor necrosis factor secretion ( J:116670 , J:116763 , J:121070 )

• after stimulation with zymosan, TNF production is significantly reduced in Myd88-deficient animals (J:116670)

• less upregulation of TNF-alpha in Plasmodium infection (J:116763)

• following treatment with PbA(Plasmodium bergbei ANKA)-parasitized erythrocytes or LPS-stimulation, TNF secretion is reduced (J:121070)

decreased inflammatory response ( J:123946 )

• in a model of induced pneumococcal meningitis-associated labyrinthitis, homozygotes exhibit a significantly lower granulocytic infiltration of the labyrinth and increased bacterial density in the cochlea at 24 hrs post-infection relative to wild-type control mice

bronchiolitis ( J:162707 )

• rMA15 SARS-CoV-infected mice show denuding bronchiolitis not seen in wild-type mice

abnormal innate immunity ( J:162707 )

• the innate immune response is severely delayed in rMA15 SARS-CoV-infected mice, with lung inflammation becoming evident at 6 dpi compared to 2 dpi in wild-type mice and delay of recruitment of inflammatory monocytes/macrophages to lungs

abnormal NK cell physiology ( J:139001 )

• NK cells fail to make IFN-gamma in response to injections of TLR9 agonists

abnormal macrophage physiology ( J:116670 )

• TNF production is impaired in thioglycollate-elicited macrophages treated with intact zymosan

• cytokine production by macrophages cultured with P. carinii cysts is reduced compared to wild-type

abnormal response to infection ( J:121070 )

• following treatment with PbA (Plasmodium bergbei ANKA)-parasitized erythrocytes, mice have a decreased immune response in terms of TNF and IL-6 secretion and response to CpG

decreased susceptibility to parasitic infection ( J:116763 )

• resistant to cerebral malaria but eventually die of extremely high parasitemia

increased susceptibility to Coronaviridae infection ( J:162707 )

• mice show increased susceptibility to infection with a recombinant mouse-adapted SARS-CoV, rMA15 , showing enhanced pulmonary pathology, higher viral loads in lung tissue, and greater than 90% mortality by 6 days post infection (dpi)

• rMA15 SARS-CoV-infected mice show extensive lung pathology, exhibiting denuding bronchiolitis and peribronchivascular edema not seen in wild-type mice and more severe perivascular cuffing

• however, infectious virus is not detected in the brain, liver, or kidney and only sporadic viral titers are seen in the spleen

increased susceptibility to Coronaviridae infection induced morbidity/mortality ( J:162707 )

• rMA15 SARS-CoV-infected mice show greater than 90% mortality by 6 dpi compared to 100% survival in controls

increased susceptibility to Picornaviridae infection ( J:97662 )

• increased susceptibility to encephalomyocarditis virus (EMCV) infection compared to wildtype

hematopoietic system

abnormal dendritic cell differentiation ( J:139001 )

• dendritic cell maturation fails to occur in vivo upon exposure to TLR9 agonists

increased dendritic cell number ( J:116763 )

• increased numbers of dendritic cells in brains of mice infected with Plasmodium

abnormal NK cell physiology ( J:139001 )

• NK cells fail to make IFN-gamma in response to injections of TLR9 agonists

abnormal T cell physiology ( J:97662 )

• induction of the antigen-specific CD8+ T-cell response by immunizing with soluble ovalbumin and TLR9 agonists, but not TLR2 and TLR6 agonists, was severely impaired

abnormal macrophage physiology ( J:116670 )

• TNF production is impaired in thioglycollate-elicited macrophages treated with intact zymosan

• cytokine production by macrophages cultured with P. carinii cysts is reduced compared to wild-type

hearing/vestibular/ear

abnormal susceptibility to hearing loss ( J:123946 )

• in a model of induced pneumococcal meningitis-associated labyrinthitis, homozygotes exhibit significantly less hearing impairment at 24 hrs post-infection in response to click, 1- or 10-kHz stimuli relative to wild-type control mice

nervous system

abnormal neuron differentiation ( J:129957 )

• improved differentiation of progenitor cells into neurons

• survival of newly formed neurons is reduced

abnormal nervous system physiology ( J:122826 )

• after cold induced cortical injury, recruitment of neutrophiles to lesion site is reduced by 85% in comparison to controls

• cold induced cortical lesion volume is reduced by 25% compared to controls

• fewer cortical cells have damaged DNA compared to controls after cold induced cortical injury

digestive/alimentary system

rectal hemorrhage ( J:128329 )

• gross rectal bleeding 5 days after induction of colonic inflammation with dextran sodium sulfate

abnormal enterocyte morphology ( J:128329 )

• increased number of apoptotic intestinal epithelial cells

renal/urinary system

decreased susceptibility to kidney reperfusion injury ( J:146120 )

• moderately protected from ischemia reperfusion injury as measured by serum creatinine levels 24 hours after injury

cardiovascular system

rectal hemorrhage ( J:128329 )

• gross rectal bleeding 5 days after induction of colonic inflammation with dextran sodium sulfate

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Coronavirus infectious disease		DOID:0080599		J:162707