2013 CLASS/POLA.Diseases of Mice.La Perle 1

PATHOLOGY OF THE
MOUSE
Krista M. D. La Perle, DVM, PhD, Dipl. ACVP
Associate Professor
Director, Comparative Pathology & Mouse
Phenotyping Shared Resource
The Ohio State University
CLASS/POLA
August 8th, 2013
ANATOMICAL
CONSIDERATIONS
http://whywouldyouknitthat.blogspot.com/2008/09/this
-is-what-happens-when-biologist.html
Brown Adipose Tissue
From ACLAM Slide Set
2013 CLASS/POLA.Diseases of
Mice.La Perle
1
Harderian Gland
Modified Sebaceous Glands:
Preputial/Clitoral
Comparative Anatomy and Histology: A Mouse and
Human Atlas, 2011
Modified Sebaceous Glands:
Zymbal’s
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Mammary Glands
99mTcO 4
Scintigraphy
www.mammary.nih.gov
Hematolymphoid




Lymphocytes predominate
Polychromasia
High platelet numbers
Hematopoiesis
 Bone marrow
 Spleen
 Liver, adrenal, LN, etc.
 Thymus doesn’t involute
 Perivascular lymphocytic aggregates
Lung
No intrapulmonary cartilage plates
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Liver
Polyploidy, anisocytosis/anisokaryosis, intranuclear cytoplasmic invaginations
Salivary Glands
Male
Female
Sexual dimorphism: Eosinophilic granules in convoluted ducts
Stomach
Comparative Anatomy and Histology: A Mouse
and Human Atlas, 2011
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Kidney
Female
Male
Sexual dimorphism: cuboidal parietal epithelium of Bowman’s capsule
Male Reproductive
Comparative Anatomy and Histology: A Mouse and
Human Atlas, 2011
www.tvmouse.compmed.ucdavis.edu
Placentation
Discoid, labyrinthine,
hemochorial
www.vivo.colostate.edu
Comparative Anatomy and Histology: A Mouse and
Human Atlas, 2011
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Adrenal Gland
X-zone, ceroid/lipofuscin
accumulation, accessory nodules,
subcapsular spindle cells
Brain
Lissencephaly
Bone
 Cortical bone = circumferential lamellae
(L) versus Haversian osteons (R)
 Longitudinal growth ceases ~3 mo.
Comparative Anatomy and Histology: A Mouse and Human Atlas, 2011
2013 CLASS/POLA.Diseases of
Mice.La Perle
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MISCELLANEOUS
DISEASES
http://weheartit.com/entry/35463576
INBRED
 Product of ≥ 20 consecutive
generations of sister x brother or
parent x offspring matings
 Single ancestral pair in the 20th or
subsequent generation
 Homozygous at virtually all loci
 Strain-distinguishing
characteristics
2013 CLASS/POLA.Diseases of
Mice.La Perle
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FVB
 Primarily used for…
 Transgenic mouse
production
 Large pronuclei
 Natural
superovulators
Intramural.nihm.nih.gov/tgc/photogallery.html
Retinal Degeneration
 Pde6brd1
 Retinal degeneration 1 mutation
 FVB, C3H, SJL, SWR, CBA, outbred swiss
 Phosphodiesterase 6b, cGMP, rod receptor,
beta polypeptide
 Blindness when homozygous recessive
Model for retinitis pigmentosa
 Nyctalopia  reduced peripheral visual field +/- loss
of central vision
 Transgene and Pde6brd1 segregate
independently
Retinal Degeneration
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Space Cadet Syndrome
 Seizures  hypoxia  neuronal
necrosis
 Spontaneous or induced by tattooing,
clipping, noise, etc.
 Cerebral cortex, hippocampus, thalamus
 Often no histologic lesions!
 Brain weight differences?
 F>M
Hernias
 Lateral femoral hernias
(FVB/NHsd; F>M)
 Comparative Medicine 58:
395-398, 2008
 Scrotal hernias (FVB/N,
closed colony, M only)
 Comparative Medicine 65:
391-394, 2012
 Other causes
 Muscle weakness
 Estrogen in males;
testosterone in females
 Genotype (fibulin 3;  IGF-3)
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Normal
Space Cadet
2013 CLASS/POLA.Diseases of
Mice.La Perle
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129
 Primarily used for…
 Targeted
mutagenesis by
homologous
recombination
 Knock-outs, knock-ins
 Embryonic stem (ES)
cell lines
 P, S, T, X substrains
Molecular Biology of the Cell, 4th Edition
Corpus Callosum
Hypo-/Aplasia
The Jackson Laboratory
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Mouse Urologic Syndrome
 Males
 Retention of
ejaculated coagulum
in urethra
 Found dead
 Urine dribbling,
ulcerative
balanoposthitis,
paraphimosis
Acidophilic Macrophage Pneumonia
 Eosinophilic crystalline pneumonia;
crystalline pneumonitis
 NMRI, T x HT, 129, C57BL/6 & B6;129
 Asthma and parasitic models
 Inhalational toxicology studies
 Pulmonary tumors and pneumocystosis
 Up to 88% incidence
 Cause of death in up to 10%
 Associated with epithelial hyalinosis
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Bronchiolar
19%
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Olfactory
Tracheal
77%
26%
Gastric
46%
Pancreatic
Biliary
11-13%
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Esophageal
Ureteral
Charcot-Leyden Crystals
 Ultrastructural resemblance
 Primates and NHPs
 Pathologies associated w/ eosinophils
 Derived from core of eosinophil granules
 Hexagonal, bipyramidal
 High in Zn, lysophospholipase
 Form directly
2013 CLASS/POLA.Diseases of
Mice.La Perle
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AMP/Hyalinosis Crystals Contain:





Iron
1-anti-trypsin
Immunoglobulin
Granulocyte breakdown products
And…..
AMP/Hyalinosis
 Ym1: Lung, spleen, BM
 T lymphocyte-derived eosinophil
chemotactic factor (ECF-L)
 Azurophilic granules in neutrophils
 Macrophages elicited by Th2 response
 Ym2: Stomach, thymus, kidney
 Precursor (55 kd; glandular) vs. mature
(45 kd; forestomach)
 Now: Chitinase 3-like 3 (Chi3l3)
Chi3l3
 Chitinase-like proteins w/o chitinase
enzymatic activity
 Chitin: Linear polymer of β-1,4-Nacetyl-D-glucosamine
 Bacteria, fungi, parasites, plants, insects
 Chitinase: Breaks down β-1,4 linkage
between CHO monomers
 Involved in recognition of endogenous
CHO polymers with similar structures,
i.e. glycosaminoglycans  abundant
 Rheumatoid arthritis, Gaucher’s disease
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Chi3l3
 Why do crystals form?
 Under what conditions do crystals
form?
 What are the biological functions?
 Is production regulated by cytokines?
Chi3l3
 Crystals form due to local [↑] 2o to
neutrophil degranulation during repeated
episodes of inflammation
 Also seen concurrently w/ neoplasms
 Th2  macrophages  phagocytosis +/rupture
 Mildly acidic pH contributes to crystallization
and phagolysosome formation
 Crystals resistant to degradation
 Inflammation, epithelial hyperplasia
Chi3l3
 Physiologic ligand = heparin /
heparan sulfate on cell surface or
ECM
 Cell-cell recognition & cell-ECM
interactions
 Matrix organization, cell adhesion,
growth factor or cytokine interaction
with cell & ECM during embryogenesis,
hematopoiesis, inflammation, tumor
metastasis
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Normal
Megaesophagus
 Impaction
 Morbidity
C57BL/6
 Primarily used for…
 Blastocyst injection
with ES cells
 Hardy
 Respond well to
superovulation
 Mouse genome
sequenced
Nature, 420, 2002
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Hydrocephalus
Malocclusion
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Cataracts ±
Microphthalmia/Anophthalmia
Also due to senility and irradiation
Corneal Opacities
 DDX: Keratitis
  ammonia levels in cage
 Ketamine anesthesia
Attenuated blink response  tear film
evaporation  exposure keratitis
 Mechanical irritation
Nudes
Rubbing eyes/face
Caging, waters
Barbering, Dalila Effect,
Trichotillomania
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Ulcerative Dermatitis
 Cause?
 F > M,  w/ age, peaks in midsummer
 Alopecia/excoriations
 Barbering, fur mite hypersensitivity, fight
wounds, wire bar lids/waterers
 Head, neck, dorsum
 Pruritis!
 Opportunistic infections with
Staphylococcus or Streptococcus spp.
dermatitis
Ulcerative Dermatitis





Immune complex vasculitis
Ulceration and skin degloving
Fibrosis and contracture
Lymphadenopathy, splenomegaly
“Treatment”







Nail trim
Antibiotics (topical, feed, water)
NSAIDs
Vitamin E (gavage with Derm Caps, diet)
Topical cyclosporine
Topical zinc oxide
Euthanize!
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Imperforate Vagina
Muco-/Hydrometra
Presbycusis
 Cdh23ahl
 Age-related hearing loss
 Cadherin 23, Age-related hearing loss 1 mutation
 Disruption and loss of inner and outer hair cell 
collapse of organ of Corti
 C57BL/6, 129, A/J, DBA
Histology: A Text and Atlas,
5th Edition
C57BL/6
 Melanosis
 Heart valves, spleen, meninges, Harderian
gland
 Taupathy
 PAS needed to visualize inclusions
 Laminin, heparan sulfate proteoglycan, tau, 
synuclein
 Osteoporosis
 Osteoarthritis
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Cardiac Calcinosis
 BALB/c (esp. ByJ substrain), SCID, C3H, DBA
 Dystrophic mineralization
 RV > LV, IVS, atria
 BALB/c – epicardial
 C3H – myocardial with degeneration
 DBA – epicardial, myocardial, soft tissue
 Increase with exogenous corticosteroids or ACTH,
high fat/low protein diets, and selenium/vitamin E
deficient diets
 Normocalcemic
 Usually no clinical cardiac dysfunction
 Von Kossa, Alizarin red special stains
Cardiac Calcinosis
2013 CLASS/POLA.Diseases of
Mice.La Perle
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NON-INBRED
 F1 Hybrids: generated by crossing 2
different inbred strains
 Outbred stocks: intentionally not bred
with siblings or close relatives to
maintain maximum heterozygosity
Nasal Septal Eosinophilic Substance
 PAS w/
diastase
positive
 Congo red
negative
 Collagen +
complex
CHO
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Hermaphroditism
 Most ES lines are XY
 Blastocysts for injection are unsexed
 Both cell types have significant
contributions to gonads
 >30% XY cells  males
 <20% XY cells  females
 20-25% XY cells  hermaphrodites
 Ovotestis/testis on left
 Ovary on right
 Cystic mullerian duct remnants
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Fibro-osseous Lesions




Tibia, femur, sternum, vertebrae, nasal bone
No renal/PTG changes
Females +/- cystic ovaries/endometrial hyperplasia
 w/ DES (estrogen) & misoprostol (PGE1 analogue)
LESIONS LACKING
STRAIN SPECIFICITY
http://www.britam.org/DNA/BAMAD82.html
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Amyloidosis
 Secondary, reactive: AA
 Macrophage activation  IL-1, IL-6 
hepatic production  proteolysis
 Spleen, liver, intestine, kidney (glomeruli)
 Primary, senile: AapoAII
 Hepatic production  no proteolysis
 Intestines, endocrine and reproductive
organs, less severe in spleen and liver
 Deposits are typically mixed
Atrial Thrombosis
 Left- or rightsided heart failure
 Common cause of
non-infectious
dyspnea
 Left auricle
 Also in BALB/c
which are
resistance to
amyloid
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Necrotizing Polyarteritis
 Murine counterpart to polyarteritis nodosa and
beagle pain syndrome
 Small- to medium-sized arteries
 Fibrinoid degeneration, neutrophilic to
lymphoplasmacytic inflammation, myointimal
hyperplasia and fibrosis
 Segmental, acute to chronic, multiple
 Immune complexes
 Cause?
 Vestibular syndrome
 DDX: Spontaneous aortitis (root) in Balb/c
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Brainstem Infarction
 Swiss mice, females, < 1-year-old
 Caudal cerebellar artery (thin)
 Branch of basilar artery (*) that emerges distal
to convergence of vertebral arteries (thick)
 Veterinary Patholology 48: 726-7289, 2011
Veterinary Patholology 48: 726-7289, 2011
Other Urinary
Disorders
 Chronic
glomerulonephropathy
 Membranoproliferative
 PAS positive
 Chronic progressive
nephropathy
 Multifocal: glomerular
hyalinosis,
glomerulosclerosis, tubular
degeneration and
regeneration, interstitial
inflammation, hyaline casts
 Hydronephrosis/-ureter
 Unilateral to bilateral
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Cystic Bulbourethral Glands
Seminal Vesicular
Dilatation or Atrophy
Ringtail
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Annular Constrictions
 Ringtail
 Dry gangrene
 Multifactorial




Genetics
 relative humidity (<40%)
 ambient temperature (>80F)
Hydration status/nutrition
 DDX
 Frostbite, mouse pox, Staph/Strep dermatitis,
suckling mice and cotton nestlets; genotype
NEOPLASTIC
DISEASES
Mouse Neoplasia
 Strain and
substrain
 Age
 Environment





Stress
Temperature
Bedding
Cage density
Altitude
 Diet
 Reproduction
 Parity
 Pups suckling status
 Endogenous
retrovirus status
 Concurrent disease
 Experimental
manipulation
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Mouse Neoplasia
 Genetically engineered mice
 Mouse Models of Human Cancers
Consortium (MMHCC)
 Consensus report & recommendations
 Lymphoid, nonlymphoid, mammary gland,
prostate gland, lung, CNS, PNS, nerve sheath,
intestine, exocrine pancreas
 Histology may be different from
neoplasms arising spontaneously
 Signature phenotypes
 Pathway pathology
 Wnt vs. ErbB2 vs. Myc
Mouse Neoplasia
 Intraepithelial neoplasia
 Atypical epithelial cells
 Precursor to cancer (molecular changes)
 May disappear, remain unchanged or
progress to cancer (high grade)
 GIN, MIN, PIN, CIN
Carcinogenesis 27: 1054-1067, 2006
EMT
 Epithelial to mesenchymal transition
 Developmental/lineage switch (?)
 Polarized epithelial phenotype  highly motile or
fibroblastoid phenotype
 Embryonic development - gastrulation
 Chronic inflammation and fibrosis
 Cancer progression and metastasis
 Loss of E-cadherin
 Gain of vimentin +/- smooth muscle actin
 Twist, snail and slug = inducing transcription factors
 Mesenchymal to epithelial transition
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Mouse Neoplasia
 Hematopoietic
 Lymphoid
 Non-lymphoid




Liver
Lung
Mammary Gland
Other
http://www.freewebs.com/mouseonawheel/tumor.htm
Lymphomas and Leukemias
 B cell
 Small, splenic marginal zone, follicular,
diffuse large, histiocyte-associated DLBC,
lymphoblastic, plasmacytoma
 T cell
 Precursor lymphoblastic, small
 129, AKR, CFW, C58, CB17.scid,
NOD/scid
 Spontaneous, MuLVs, chemicals,
irradiation, genetically engineered
 Leukemia: Blood, bone marrow
Lymphomas/Leukemias
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Lymphomas/Leukemias
Lymphomas/Leukemias
Lymphomas/Leukemias
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Lymphomas/Leukemias
Differential: SCID with severe Corynebacterium bovis-associated
hyperkeratosis and secondary bacterial infection
Plasmacytomas
 Intraperitoneal
injection of
mineral oil,
pristane,
plastics, other
foreign
material
 BALB mice
Granulocytic Leukemia
 Retroviruses,
carcinogens,
irradiation
 Spleen  widespread
 Anemia
 WBC >200,000
 Grossly may appear
green
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Acute Tumor Lysis Syndrome
 Rapid destruction of malignant cells 
massive release of cellular
contents/breakdown products  acute
metabolic crisis
 High P, K, uric acid; hypocalcemia
 Death  cardiac arrest, hypoxia
 Lymphoid neoplasms, granulocytic
leukemia
 Chemotherapy, corticosteroids, hormones,
cytokines
 Spontaneous
Acute Tumor Lysis Syndrome
Histiocytic Sarcomas
 SJL and aging B6
 Reticulum cell sarcoma, histiocytic lymphoma,
MFH, malignant histiocytosis, Kupffer cell sarcoma
 Incidence: 1-22% depending on strain
 Liver, uterus
 Mononuclear-phagocytic cells
 Hyaline droplets  kidney
 Overproduction of lysozyme  saturation of lysosomal
hydrolytic enzymes
 Granulocytic leukemia, B cell LSA
 EMH  spleen, liver
 Dysmyelopoiesis (↓M; ↑E)  BM
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Histiocytic Sarcomas
Histiocytic Sarcomas
Histiocytic Sarcomas
 Also seen with
granulocytic
leukemia and
B cell
lymphomas
 ChromotropeAniline Blue +
Toxicologic Pathology
31: 462-464, 2003
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Hepatocellular Lesions
 Foci of cellular alteration (basophilic, eosinophilic,
clear)
 Altered staining properties, no alterations in liver
architecture, no compression of parenchyma
 Regenerative hyperplasia
 Prior or ongoing hepatocellular damage
 Hepatocellular adenoma/hepatoma and carcinoma
 Trabecular, solid, adenoid
 Hepatoblastoma
 Spontaneous, hepatocarcinogens, Helicobacter
hepaticus
Foci of Cellular Alteration
Phenobarbital
 -glutamyl transferase
Diethylnitrosamine
 glucose-6-phosphatase
International Classification of Rodent Tumors
Hepatocellular Tumors
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Hepatocellular Tumors
Nodular Hyperplasia
Adenoma
Carcinoma
International Classification of
Rodent Tumors
Hepatoblastomas
 Rare (<1%)
 Arise w/in or adjacent
to adenomas/CAs
 Distant mets,
including lungs
 Diethylnitrosamine /
phenobarbital
 Cell of origin?
 Oval, hepatocytes,
biliary epithelium
Pulmonary Tumors
 Common in older mice
 GR, BALB, A/J, FVB strains
 K-ras
 Bronchogenic tumors  hilus
 Not reported in mice
 Bronchiolar/alveolar tumors  periphery
 Bronchiolar tumors originate from Clara cells
 Alveolar tumors originate from type II pneumocytes 
surfactant production
 Current recommendation: pulmonary adenoma or
carcinoma, specify solid, papillary or mixed
 Hyperplasia  adenomas > carcinomas
 Must differentiate from metastatic tumors
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Pulmonary Tumors
Pulmonary Tumors
Mammary Tumors
 Strain dependant  C3H
 MuMTVs
 Endogenous
 Exogenous – removed by rederivation
 Bittner agent: intentionally maintained in C3H
 Carcinogens, prolactin, estrogen,
progesterone
 Stress, ad libitum feeding
 Glandular, acinar, cribriform, papillary,
solid, squamous, fibroadenoma,
adenomyoepithelioma, adenosquamous
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Pituitary Gland Tumors
 FVB/N
 Persistent mammary gland hyperplasia +/squamous nodules
 Hyperplasia or adenoma of pars distalis
 Acidophils/lactotrophs
 Upwards of 50% incidence by 18 mo.
 Mammary carcinomas in multiparous mice with
prolactinomas
 Adenosquamous differentiation
 EMT
 ER immunoreactivity
Comparative Medicine 53: 424-432, 2003
Pituitary Gland Tumors
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Comparative Medicine 53: 424-432, 2003
Salivary Gland Myoepitheliomas
Multiple strains of mice, especially BALB
Females > males
Submaxillary and parotid
+/- mammary, preputial and Harderian
gland tumors
 Pulmonary metastasis with large tumors
 Myeloid hyperplasia  tumor secretory
product




2013 CLASS/POLA.Diseases of
Mice.La Perle
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Salivary Gland Myoepitheliomas
Harderian Gland Tumors
 Hyperplasia  adenoma
 adenocarcinoma
 Papillary, cystic, acinar
 Unilateral or bilateral
 Old albino and pigmented
strains
 0.5-14.9% incidence
 Spontaneous, irradiation,
carcinogens
Harderian Gland Tumors
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Hemangiomas/
Hemangiosarcomas
 Anywhere!
 Liver, uterus, skin, spleen, bone
marrow
 Ovary
 DDX: Angiectasia
 Thrombosis seen in both
 Multicentric or metastasis?
 Metastasis to lungs
Hemangiosarcomas
Angiosarcomas
2013 CLASS/POLA.Diseases of
Mice.La Perle
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SQ Neural Crest Tumors
FVB Mice: Pinna/Tail
Teratomas
129 Mice
Teratomas
Neuro/Ectoderm
Mesoderm
2013 CLASS/POLA.Diseases of
Mice.La Perle
Endoderm
45
INFECTIOUS
DISEASES
http://www.point64.com/apm/10152004cute_
mouse.html
BACTERIA
http://www.ehow.com/about_5380594_bacteria-life-cycle.html
Citrobacter rodentium





Gram negative bacilli
Transmissible murine colonic hyperplasia
Direct contact, fecal-oral
Transient SI colonization
Attachment to descending colon
 Bacterial intimin and translocated intimin
receptor (Tir)
 Dissolution of brush border, actin rearrangement,
pedestal formation
 Like attaching and effacing EPEC & EHEC  model!
2013 CLASS/POLA.Diseases of
Mice.La Perle
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Citrobacter rodentium
 Bacterial colonization illicits mucosal
hyperplasia
 Displace infected cells as hyperplastic cells
migrate to surface
 Peak 2-3 weeks post-infection
 Lesions resolve by ~2 months
 Immune response important in
clearance/recovery and disease severity
 CD4 and Th1 response
 MAIDS, Veterinary Pathology 47: 312-317,
2010
Citrobacter rodentium





Thick colon, shrunken cecum, no feces
Long crypts
Epithelial hyperplasia
Loss of goblet cells
Variable erosion/ulceration and
inflammation
 No known carrier state in
immunocompetent
 Recovered mice refractory to infection
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E. coli
 Atypical, non-lactose fermenting, gram
negative bacilli
 Colonic hyperplasia
 Segmental
 Immunodeficient mice
 Bacteria in gut lumen, attached to
surface and within enterocytes
 Primary pathogen?
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Helicobacter spp.
 MAJOR GI pathogens in rodents!
 H. hepaticus, H. bilis
 Also H. rodentium, H. muridarum, H.
typhlonius, H. ganmani, H. rappini, H.
mastomyrinus
 Gram negative, spiral bacilli
 Transmission: Fecal-oral, bedding
 Serology
 Fecal PCR preferred
 Helicobacter genus
 Differentiate species
Helicobacter spp.
 Pathogenicity
 Immunodeficient: Nudes, SCIDS, rag KOs, IL-10 KO
 A and C3H strains
 Age and sex (M>F)
 Typhlocolitis +/- colonic tumors
 Hepatitis +/- hepatocellular tumors
 Biliary canaliculi
 Gastritis, gastric atrophy, MALT lymphoma
 Also experimental H. pylori, H. felis, H. suis infection
 Rederivation or foster pups (w/in 24 hours) >>>
medicated feed
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40x
20x
40x
20x
40x
Clostridium piliforme
 Intracellular, gram negative, sporeforming, filamentous bacilli
 Tyzzer’s disease
 “Species-specific”
 Ingest spores which remain infective
for long periods in environment
 Poor husbandry, immunosuppression
 Organisms invade intestinal epithelium
 dissemination
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Clostridium piliforme




Necrotizing hepatitis
Necrotizing enterotyphlocolitis
+/- Necrotizing myocarditis
Warthin-Starry silver stain
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Salmonella spp.
 S. enterica subsp. enterica


Serovar typhimurium  S. typhimurium
Serovar enteritidis  S. enteritidis
 Rare
 Transmission: fecal-oral, fomites +/- vertical
 Fimbrial attachment to M cells  phagocytosis by
enterocytes  multiples in GALT and LNs  systemic


Readily killed by neutrophils
Evade clearance in macrophages
 Liver, spleen, intestines
 Biofilms
 Intermittent fecal shedding  carrier  zoonotic!
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Corynebacterium bovis
 Coryneform-associated hyperkeratosis
 Immunodeficiency + hairlessness
 SCID mice are also susceptible!
 Xenograft studies
  tumor growth
  toxicity of chemotherapeutic agents
 Direct transmission, fomites
 Culture or PCR
 Skin, oropharynx, blood
 SLOW growing – hold for 7 days
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Corynebacterium bovis
Orthokeratotic hyperkeratosis
Acanthosis
Sparse dermatitis
+/- gram positive rods within stratum
corneum
 Weight loss




 Dehydration
 Anorexia
 DDX: Low ambient humidity
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Staphylococcus spp.




S. aureus
S. xylosus
Commensal
Suppurative to pyogranulomatous
 Splendore-Hoeppli
 Necrotizing to ulcerative
 Burn-like lesions
 Gram positive cocci
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Differentials: Trauma,
mechanical denudation
(cages, waterers), thermal
or chemical burns
Differentials: Corynebacterium kutscheri, Streptococcus spp., Pasteurella
pneumotropica, Pseudomonas aeruginosa
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Rhinitis/Otitis/Septicemia








CAR bacillus
Bordatella hinzii
Mycoplasma pulmonis
Pasteurella pneumotropica
Pseudomonas aeruginosa
Streptococcus spp.
Burkholderia gladioli, cepacia
Klebsiella oxytoca
Rhinitis/Otitis/Septicemia




Gram negative bacteria
Commensals
Environmental contaminants
Immunodeficiency
 C3H/HeJ: defective Toll-like receptor 4
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C
EAM
TC TM
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VIRUSES
EDIM
 Epizootic diarrhea of infant mice
 EDIM strain of Rotavirus A
 All ages susceptible but disease limited
to <2 weeks of age
 Infects terminally differentiated
enterocytes in SI/LI
 Most plentiful and widespread in neonates
  #, distribution and differentiation as gut
microflora established
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EDIM
 Transmission: fecal-oral
 Clinical signs in naïve population
 Complete recovery ~14-17 days of
age
 Runting, diarrhea, steatorrhea, potbellied
 Still suckle!
 Fluid-filled bowel
 Hydropic vacuolar degeneration of
enterocytes in villar tips
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Murine Hepatitis Virus
 Coronavirus
 Multiple strains based on virulence and
organotropism
 Respiratory strains = primary tropism for
respiratory mucosa but polytropic
 Enterotropic strains = selective infection
of intestinal epithelium, even in
immunodeficient
 Susceptible strains: C57BL, DBA,
nude, SCID, BALB/c
Polytropic MHV
 Virulent strains, mice <2 weeks of age,
immunodeficient
 CNS, liver, lymphoid tissues, bone
marrow, endothelium
 Necrosis
 Syncytitia
 Particularly common in immunodeficient
Nude mouse w/ MHV
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Enterotropic MHV
 All ages susceptible
 Disease in neonates
 Lethal intestinal virus of infant mice (LIVIM)
 Minimal disease in adult nudes/SCIDs
 All strains susceptible, including those
resistant to polytropic MHV
 Necrotizing enteritis
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Ectromelia Virus
 Mousepox (orthopox)
 Missing limbs
 Pathogenesis
 Cutaneous invasion  local replication 
regional lymph nodes  primary viremia
 replication in spleen and liver 
secondary viremia systemically
 Highly infectious
 Immunocompetent: subclinical;
recovery; no carrier state
Ectromelia Virus
 Immunodeficient!
 Acute and rapidly fatal
 Necrosis and hemorrhage
 Liver, lymphoid organs, epithelium
 Chronic
 Cutaneous ulceration and gangrenous
necrosis of feet, tail, snout
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Mouse Parvovirus
Mice minute virus (MMV)
Mouse parvovirus (MPV) (75%)
Mixed infections
Seroconversion but no clinical disease in
immunocompetent
 Immunomodulatory effects
 Hard to eradicate




Mouse Parvovirus
 Oronasal exposure
 Dependent on S-phase of cell cycle for
replication  rapidly dividing cells
 Initially replicates in SI intraepithelial
lymphocytes, lamina propria and
endothelium  systemic
 No intestinal disease
 Hematopoietic tissue  myeloid and
lymphoid +/- erythroid
Mouse Norovirus
 Caliciviridae
 Norwalk virus  1st
 Cruise ship gastroenteritis
 Emerging pathogen (2003)
 Persistent infection w/ no evidence of
pathogenicity in immunocompetent
 Clinical disease +/- mortality in
compound immunodeficient mice
 Acquired (Rag1KO) & innate (STAT1KO,
IFN R KO) immunity
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Mouse Norovirus
 High seroprevalence (35%)
 Persistent shedding
 Multiple strains
 Transmission: fecal-oral
 Following PO, IN, IC exposure
 Replicates in macrophages of lung, liver,
lymphoid organs
 Variable pathology
 Alveolitis/interstitial pneumonia,
hepatocellular necrosis, splenitis
Murine Retroviruses
 Retroelements make up ~37% of
mouse genome






Mother Nature’s transgenes!
Gag: capsid and nucleoproteins
Pro: protease (Gag protein cleavage)
Pol: reverse transcriptase and integrase
Env: surface glycoprotein
Flanked by LTRs
http://microbewiki.kenyon.edu/index.php
/Koala_Retrovirus
Murine Retroviruses
 Endogeneous
 Exogenous
 Most eliminated by rederivation/crossfostering
 Replication competent or incompetent
 Integrate into genome (proviruses)
 Most are defective/silent
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Murine Retroviruses
 Tropism




Ecotropic: mouse
Xenotropic: all except mouse
Amphotropic
Polytropic: all but…
 Distinct receptor
 Restricted host range
Murine Retroviruses
 Transmitted via milk, semen, saliva,
vertical
 Moloney murine leukemia virus
(MuLV)
 Lymphomas/leukemias
 Granulocytic leukemia
 Hind limb paralysis/neuronal
degeneration in wild strain
Murine Retroviruses
 Mouse mammary tumor virus (MMTV)
 Mammary tumors
 Lymphocytotropism and lymphoid
transformation
 Bittner agent, MMTV-S,
extrachromosomal milk factor =
exogenous (C3H)
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Murine Papillomavirus
 Veterinary Pathology 48:
500-505, 2011
 NMRI-FoxnInu / FoxnI
 PCR  novel MusPV
 Transmissible
Differentials: Carcinogens, genotype
FUNGI
http://www.biologyjunction.com/fungi_notes_b1.htm
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PLoS Pathogens
6: e1001009, 2010
Pneumocystis murina







Species-specific
Ubiquitous
Asexual: binary fission  trophic form
Sexual  ascus w/ 8 ascospores
Pathogenic if immunodeficient
Asymptomatic
Dyspnea, rough hair coat, dyspnea,
cyanosis, death
Pneumocystis murina
 Inhalation of asci
 Ascospores released in alveoli
 Attachment to type I pneumocytes and
macrophages by fibronectin-binding
integrins
 Necrosis of pneumocytes w/ damage to
alveolar basement membranes
 Type II pneumocyte hyperplasia
 Proposed: Pneumocystis binds to
surfactant protein altering function
Dr. Nozomi Shimonohara, Purdue University, 2009 MAVP
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Dr. Nozomi Shimonohara, Purdue University, 2009 MAVP
Alveolar wall and trophic forms
Cyst form
Dr. Nozomi Shimonohara, Purdue University, 2009 MAVP
PARASITES
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Fur Mites = Acariasis
 Myobia musculi
 Head, neck, shoulder
 Feeds on skin secretions and interstitial fluid
 Type I hypersensitivity (B6)
 Myocoptes musculinus
 Most common
 Superficial epidermis
 Inguinal, ventral abdomen, back
 Radfordia ensifera (rat fur mite)
 Mixed infections
Fur Mites = Acariasis




Direct life cycle, ~ 3 weeks long
Egg, nymph, adult stages on mouse
Eggs laid on hair shaft
Direct transmission
 Suckling mice at 1 week of age
Pelage eruption
 Hairless (nude) mice not susceptible
Fur Mites = Acariasis





Alopecia, erythema, pruritus
Ulcerative dermatitis
Reduced life span, weight loss, infertility
Pelt exam
Skin scrape/tape test
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Myobia
Radfordia
Myocoptes
Slightly elongated
body
Slightly elongated
body
Oval, egg occupies ½
of abdomen
Bulges between legs
Bulges between legs
Heavily chitinized,
pigmented 3rd & 4th
legs
2nd pair of legs: single
terminal tarsal claw
2nd pair of legs: 2
terminal tarsal claws of
unequal length
1st pair of legs
Suckers on tarsi
♂
Bulges
between
legs
Heavily
chitinized
pigmented
3rd & 4th
tarsi
Slightly elongated body
Myobia musculi
♀
Myocoptes musculinus
Pinworms = Oxyuriasis
 Syphacia obvelata
 Direct life cycle, 12-15 d long
 Adults in cecum and colon
 Eggs laid in perianal area; infective within hours
 Aspiculuris tetraptera
 Direct life cycle, 23-25 d long
 Adults in cecum and colon
 Eggs passed in feces; infective at RT x 6-7 d
 Syphacia muris (rat pinworm)
 Mixed infections
 Environmental resistance
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Pinworms = Oxyuriasis
 Asymptomatic
 Rectal prolapse, intussusception, fecal
impaction, diarrhea, poor weight gain,
rough hair coat
 Catarrhal enteritis, hepatic granulomas,
perianal irritation
 Young, males, immunodeficiency (nude)
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Pinworms = Oxyuriasis
 Tape test
 Fecal float
 Aspiculuris
Bilaterally
symmetrical
Unembryonated
 Syphacia
Banana-shaped
Embryonated
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Aspiculuris
Syphacia
Spironucleus muris
 Flagellated binucleate protozoan
w/ direct life cycle
 SI, cecum
 Commensal
 Diarrhea in young, stressed,
immunodeficient
 Trophozoites ± crypt dilation,
crypt abscesses,
lymphoplasmacytic inflammation
 Recovery  asymptomatic
carriers
 Interspecies transmission
Tapeworms
 Rodentolepis nana
 Hymenolepis diminuta
 Rodentolepis
microstoma
 Zoonotic, direct
lifecycle
 Arthropod (beetles,
fleas, moths)
intermediate host
 Cysticerci in lamina
propria, adults in lumen
http://en.wikipedia.org/wiki
/File:H_nana_adultF.JPG
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Differentials
 Necrotizing
polyarteritis
 Otitis media
 Brainstem infarction
(Swiss Webster)
 Brain neoplasm
 Genotype
Neuroscience Research 72: 296-305, 2012
Differentials
 Neural crest tumor
(FVB)
 Auricular chondritis
 Monel metallic ear tags
 Experimental model of
relapsing polychondritis
 Squamous cell
carcinoma
 Fibrosarcoma
Differentials
Pneumocystic murina
Acidophilic macrophage pneumonia
Alveolar lipo-/proteinosis
Pneumonia (paramyxo) virus of mice
Sendai (paramyxo) virus in
immunodeficient mice
 Mouse Norovirus in immunodeficient mice





2013 CLASS/POLA.Diseases of
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Differentials








Clostridium piliforme
Salmonella spp.
Helicobacter hepaticus
Ectromelia (mouse orthopox) virus
Polytropic mouse hepatitis virus
Reovirus-3 (neonates)
Cytomegalovirus (neonates)
Adenovirus (neonates)
Differentials
 Enterotropic mouse
hepatitis virus
 Rotavirus A
 Salmonella spp.
 Clostridium piliforme
 Reovirus-3
 Mouse Norovirus
(immunodeficient)
 Spironucleus muris
Differentials
 Helicobacter spp.
 Citrobacter rodentium
 Atypical E. coli in
immunodeficient mice
 Pinworms
 Syphacia obvelata
 S. muris
 Aspiculuris tetraptera
2013 CLASS/POLA.Diseases of
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References-1
References-2
Acknowledgements









Sheree Beam
Charlie Clifford
Chelsea Martin
Hai Nguyen
Brett Saladino
Trenton Schoeb
Teresa Southard
Uncited Individuals
Cornell University
College of Veterinary
Medicine/Dr. John M.
King’s Necropsy Show
& Tell
Michael Eckhaus
Dean Percy
Duncan Russell
Nozomi Shimonohara
Paul Stromberg
ACLAM Lab Animal
Medicine and Science
Series II
 Joint Pathology
Conference - VSPO
 University of Georgia
College of Veterinary
Medicine Noah’s Arkive






2013 CLASS/POLA.Diseases of
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Thank You!
??
La-perle.1@osu.edu
614-292-5480
www.vet.osu.edu/CPMPSR
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