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DISEASES
OF RATS
Bacteria
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 11th, 2014
http://www.ehow.com/about_5380594_bacteria-life-cycle.html
Mycoplasma pulmonis
Mycoplasma pulmonis
 Murine respiratory mycoplasmosis (MRM)
 Chronic respiratory disease (CRD)
 Multifactorial
 Suppurative exudate, abscessation
 Strain, age
 Concurrent infections, nutritional status
 Environmental factors
 Transmission: direct contact, aerosol,
intrauterine
 Respiratory tract, middle ear,
endometrium, joints
2014 CLASS/POLA.Diseases of
Rats.La Perle
 Bronchiolitis/bronchiolectasis
 Lymphoid cuffing
 CAR bacillus = frequent co-pathogen
 Pathogenesis
 Release of cytotoxic substances
 Ciliostasis and ciliolysis
 Intact organisms and cell membranes are
mitogenic for lymphocytes
 Bystander effect from host leukocytes
1
Mycoplasma pulmonis
 Veterinary Pathology 46: 952-959, 2009
 “Lymphomas” in rat in bioassays
(Europe)
 Aspartame, methyl-tertiary-butyl ether,
methanol





2014 CLASS/POLA.Diseases of
Rats.La Perle
Pleomorphic but immunoblastic
Bronchopneumonia
Lungs
Rats were not SFP!
Slides not provided for review
2
Mycoplasma pulmonis
 Lack a cell wall
 Fastidious
 Selective media for
enrichment
 Keep for ~2 weeks
 Cross-reactive
antigens between M.
neurolyticum and M.
arthritidis
http://www.hpacultures.org.uk/
services/mycotestingeradication/
mycocultureisolation.jsp
CAR Bacillus
 Cilia-associated respiratory bacillus
 Transmission: direct contact, fomites
 Synergistic with other respiratory
pathogens (Mycoplasma pulmonis)
 Gram negative bacilli among cilia
 Warthin-starry positive
 Bronchi-/bronchiolectasis
 Lymphoid cuffing
 Suppurative bronchopneumonia
2014 CLASS/POLA.Diseases of
Rats.La Perle
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Corynebacterium kutscheri




Pseudotuberculosis
Gram positive bacilli
Transmission: direct contact, oronasal
Asymptomatic carriers - persistent
infection
 Oral cavity
 Lymph nodes
 Systemic suppurative inflammation w/ necrosis
 Random/embolic (liver, lung, kidney)
 Prominent bacterial colonies within lesions
2014 CLASS/POLA.Diseases of
Rats.La Perle
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Streptococcus pneumoniae
 Gram positive diplococcus
 Transmission: direct contact, aerosol
 Human carriers
 Systemic serofibrinopurulent
inflammation
 Pathogenesis
 Polysaccharide capsule
 Resistant to phagocytosis
 Activation of alternative complement pathway
 Serotyping
Streptococcus agalactiae
 Comparative Medicine 63: 55-61, 2013
 Β-hemolytic, Lancefield group B
 Munich Wistar Frömter X F344
 Transgenic for human diptheria toxin receptor
driven by podocin promoter
 38.5% of 21-24 day-old rats
 Spontaneous myocardial necrosis,
glomerulonephritis, abscesses, bacteria +/inflammation
 Resembles late-onset postnatal GBS infection
in human infants
2014 CLASS/POLA.Diseases of
Rats.La Perle
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Clostridium piliforme
Clostridium piliforme
 Intracellular, gram negative, sporeforming bacilli
 Tyzzer’s disease
 “Species-specific”
 Post-weaning adolescent rats
 Ingest spores which remain infective for
long periods in environment
 Poor husbandry, immunosuppression
 Organisms invade intestinal epithelium 
dissemination
 Necrotizing hepatitis
 Necrotizing enterotyphlocolitis
2014 CLASS/POLA.Diseases of
Rats.La Perle
 Megaloileitis
 Necrotizing myocarditis
 Warthin-Starry silver stain
6
Viruses
Coronaviruses
 Sialodacryoadenitis virus, rat (Parker’s)
coronavirus
 Transmission: aerosol, direct contact,
fomites
 Hi morbidity, low mortality
 Salivary, Harderian and lacrimal glands
 Rhinitis, tracheitis, bronchiolitis,
alveolitis
2014 CLASS/POLA.Diseases of
Rats.La Perle
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2014 CLASS/POLA.Diseases of
Rats.La Perle
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2014 CLASS/POLA.Diseases of
Rats.La Perle
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Paramyxoviruses
 Enveloped ssRNA viruses
 Transmission: aerosol, direct contact
 Sendai virus (parainfluenza type 1 group)
 Rhinitis, bronchiolitis, alveolitis with
epithelial proliferation, lymphoid cuffing,
interstitial fibrosis
 Additive effect with M. pulmonis
 Pneumonia virus of mice
 Nonsuppurative vasculitis and interstitial
pneumonia
2014 CLASS/POLA.Diseases of
Rats.La Perle
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Parvoviruses
 Nonenveloped ssDNA viruses
 Kilham’s rat virus (RV), Toolan’s H-1 virus,
rat minute virus (1a-1c), rat parvovirus 1
and 2
 Transmission: oronasal, transplacental,
milk, feces, fomites
 Persistence and reactivation
 Dividing cells (S) for replication 
cytolysis (NS1 and NS2)
Parvoviruses
 Endothelial cells and megakaryocytes
 Hemorrhage, thrombosis, necrosis
 Cerebellar cortex, periventriculus
 Cerebellar hypoplasia
 Hepatocytes
 Vacuolar degeneration
 Intranuclear inclusion bodies
 Decreased fertility, fetal resorption,
small litters, runts
2014 CLASS/POLA.Diseases of
Rats.La Perle
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2014 CLASS/POLA.Diseases of
Rats.La Perle
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Hantaviruses
http://mansurovs.com/tag/yosemite-nationalpark
Fungi
 Transmission: feces, urine, saliva
 Other bunyaviridae: arthropod-borne
 No clinical signs in rodents
 ZOONOTIC  Yosemite
Hantaviruses
Geographic
Range
Reservoir
http://emedicine.medscape.com/
article/788980-overview
Pathology
Mortality
Hantaan
Asia
Field mouse
Renal
5-15%
Seoul
Worldwide
Domestic
rat
Renal
1%
Puumala
N. Europe
Bank vole
Renal
1%
Prospect Hill
U.S.A.
Meadow
vole
None known
N/A
Sin Nombre
N. America
Deer mouse
Pulmonary
50%
http://www.biologyjunction.com/fungi_notes_b1.htm
http://www.cdc.gov/hantavirus/technical/hanta/virology.html
PLoS Pathogens
6: e1001009, 2010
Pneumocystis







P. carinii
P. wakefieldiae sp. nov.
Species specific
Ubiquitous
Asexual: binary fission  trophic form
Sexual  ascus w/ 8 ascospores
Initially: pathogenic if immunodeficient
 Athymic nude rats
Pneumocystis
 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
2014 CLASS/POLA.Diseases of
Rats.La Perle
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Alveolar wall and trophic forms
Dr. Nozomi Shimonohara, Purdue University, 2009 MAVP
Cyst form
Dr. Nozomi Shimonohara, Purdue University, 2009 MAVP
“Rat Respiratory Virus”
 Emerging disease (1997)
 Worldwide distribution
 6% incidence in North America via histopath;
18% via serology/PCR
 Lymphohistiocytic interstitial pneumonia w/
perivascular lymphocytic cuffing
 Causative agent identified as Pneumocystis
carinii in fall 2010
 Pneumocystis DNA by PCR in 87% of
paraffin-embedded lung lesions attributed to
RRV
 Koch’s postulate
Veterinary Pathology 46: 992-999, 2009
2014 CLASS/POLA.Diseases of
Rats.La Perle
Veterinary Pathology 46: 992-999, 2009
14
Veterinary Pathology 46: 992-999, 2009
Veterinary Pathology 46: 992-999, 2009
Comparative
Medicine 61:
45-52, 2011
Mild @ 3 wks; severe @ 5 wks; resolved by 7 wks
Comparative Medicine 61: 45-52, 2011
Pneumocystis/RRV
 Immunocompetent rats
 Similar lesions in immunocompetent mice
Parasites
 P. murina
 P. jirovecii in immunocompetent humans




SIDS
COPD
Asthma
Bronchiolitis
2014 CLASS/POLA.Diseases of
Rats.La Perle
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Cysticercus
fasciolaris
 Larval stage of cat
tapeworm
 Taenia taeniaformis
 Ingestion of eggs in
cat feces
 1-2 cysts in liver
 Granulomatous
inflammation,
fibroplasia 
fibrosarcoma
http://www.pet-informed-veterinary-adviceonline.com/tapeworm-in-cats.html
Trichosomoides crassicauda
 Bladder threadworm
 Urinary bladder and renal pelvis
 Embryonated, bi-operculate, brown eggs
 Passed in urine
 Hatch in stomach  systemic
 Only larvae reaching urinary system survive
 White masses
 Epithelial hyperplasia
 Paucity of inflammation
 “Association” w/ calculi and neoplasia
2014 CLASS/POLA.Diseases of
Rats.La Perle
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Aging Lesions
How Old is an Old Rat?




Sexual maturity (8-12 weeks)
≥14 months
≥30 months
Older than 50% survival age
 27-30 months
Factors That Alter
Longevity & Pathology
 Pathogen status
 “Dirty” rats vs. SPF
 Chronic respiratory disease
 Diet
 Ad libitum vs. caloric restriction
 Composition
 Fat, protein
 Breeding
 Retired breeders vs. virgins
Cause of Death
 Rarely attributable to “old age”
 Develop multiple neoplastic and nonneoplastic conditions
 Morbidity
 Mortality
2014 CLASS/POLA.Diseases of
Rats.La Perle
Chronic Progressive
Glomerulonephropathy
 Chronic progressive nephrosis; chronic
nephrosis; glomerulosclerosis;
progressive glomerulosclerosis;
glomerulonephritis; chronic nephritis;
nephropathy; old rat nephropathy
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Chronic Progressive
Glomerulonephropathy







≥75% incidence
Age: ≥12 months
Sex: M (castration = protective)
Strain: Sprague Dawley & F344
Diet: ad libitum, high protein
Immune: mesangial IgM deposition
Hormones: high prolactin
 Chronic prolactin: no  in specific gravity, pH,
volume, K;  Na
 Inhibition:  volume, pH, K & Na excretion
 Impaired renal degradation; pituitary neoplasia
Proteinuria
Chronic Progressive
Glomerulonephropathy
Hypoproteinemia, proteinuria
Azotemia
Hypercholesterolemia
Weight loss
Hydrothorax, ascites
Soft-tissue mineralization
2o hyperparathyroidism  fibrous
osteodystrophy
 Hypertension
 Polyarteritis nodosa







2-globulin
 Synthesized in liver under multihormonal control






Normal
Rats & mice
Higher in M>F
Albumin
2-globulin
Androgens and glucocorticoids 


T3/T4, insulin, GH
Estrogens 
 Glomerular filtration (18,700 Da)
 Males only: not in normal adult females or immature
males


Ovariectomized females  repeated testosterone injection
Not in NBR male rats
 ½ reabsorbed via endocytosis in S2 of PCT (poorly
hydrolyzable)
 Compounds (organic hydrocarbons)/metabolites bind
reversibly to 2-globulin  effectiveness of lysosomal
proteases  hyaline droplet nephropathy

Apoptotic necrosis
Basophilic Tubules: Precursor Lesion
Toxicologic Pathology 32: 171-180, 2004
2014 CLASS/POLA.Diseases of
Rats.La Perle
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2014 CLASS/POLA.Diseases of
Rats.La Perle
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Chronic Progressive
Glomerulonephropathy
 Changes in ECM:
 Generalized thickening of BMs  laminins
  ECM in interstitium  fibronectin and
thrombospondin
 Interstitial scarring in areas of tubular
atrophy
Nephrocalcinosis









F344, BD1X
Microlithiasis
>3% incidence
F>M
 magnesium
 calcium
 phosphorus
 calcium:phosphorus
Calcium phosphates at corticomedullary
junction
Hydronephrosis
 Hereditary








Brown Norway
Gunn
Sprague Dawley
Zucker
Spontaneous
Males
Polygenetic
Right kidney in males
Am J Physiol Heart Circ Physiol 293: H292–H298, 2007
 Passage of internal spermatic
vessels across ureter
Urinary Calculi
 Renal pelvis, ureter, bladder, urethra
 Variable composition
 ammonium magnesium phosphate
(struvite); carbonate, oxalate;
carbonate-phosphate, magnesium,
calcium
 Genetic
 Retinoid supplementation,
radionuclides
 Ddx: copulation plug!
2014 CLASS/POLA.Diseases of
Rats.La Perle
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Hematuria/Renal Papillary
Hyperplasia
“Spit on Cornell
University!”
 Lewis X Brown
Norway
 M>F
 +/- uni- or
bilateral
hydronephrosis
Struvite (O)
Oxalate
Cysteine
Urates (L)
Polyarteritis Nodosa





Periarteritis
60% incidence
Sprague Dawley, SHR, ACI
M>F
Medium-sized arteries: mesentery, pancreas,
pancreatico-duodenal, testes
 Not lung!
 Spontaneous, immune-mediated, chronic
nephropathy, drug-induced
 Fibrinoid degeneration, inflammation (esp.
adventitia), aneurysm, thrombosis,
recanalization, rupture
Comparative Medicine 57: 370-376, 2007
2014 CLASS/POLA.Diseases of
Rats.La Perle
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Comparative Medicine 57: 370-376, 2007
Cardiomyopathy
 Murine progressive cardiomyopathy, chronic
progressive cardiomyopathy, myocardial
degeneration and fibrosis
 ≥25%
 Sprague Dawley
 M>F
 Ad libitum
 Little evidence of cardiac insufficiency
 LV, papillary muscle, IVS
 Degeneration, interstitial mononuclear cells,
atrophy, fibrosis, mineralization,
cartilaginous/osseous metaplasia
2014 CLASS/POLA.Diseases of
Rats.La Perle
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Miscellaneous CV Lesions
 Intracardiac thromboses
 LA >> RA > LV
 Valvular endocardiosis
 No clinical signs
 Arterio-/atherosclerosis
 Hypertension
 40%
 M>F
 Renal disease, polyarteritis nodosa
 Endocardial/subendocardial proliferations
 Hyperplasia vs. sarcoma
 Infiltration into myocardium
Alveolar Histiocytosis
 Subpleural histiocytes containing:
 FFA, cholesterol, phospholipids
 Not infectious!
 Resolved inflammation
 Rat coronavirus/SDAV
 Localized pulmonary clearance deficit
 Pulmonary injury  type II pneumocyte
hyperplasia  surfactant overproduction 
accumulation in macrophages
2014 CLASS/POLA.Diseases of
Rats.La Perle
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Spontaneous
Radiculoneuropathy
Spontaneous
Radiculoneuropathy
 Degenerative myelopathy
 75-90%
 Posterior paresis, loss of tail control,
urinary incontinence
 Bilaterally symmetrical
 T4-L4 (lateral & ventral funiculi), cauda
equina, ventral spinal nerve roots, sciatic &
brachial plexus, lower brainstem
 Delayed onset but no change in incidence
w/ calorie restriction
 Axonal swelling
(spheroids)
 Axonal sheath
swelling
 Axonophagia
 Astrogliosis
 Demyelination
 Lipofuschin
 Muscle atrophy
Aging Rat Liver








Ploidy & Multinucleation
INIB
Similar to mouse
Polyploidy
Karyomegaly
Binuclear hepatocytes
IN cytoplasmic inclusions
IC inclusions
Bile duct hyperplasia
Foci of cellular alteration
2014 CLASS/POLA.Diseases of
Rats.La Perle
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Miscellaneous Lesions
Phenobarbital
 -glutamyl transferase
Diethylnitrosamine
 glucose-6-phosphatase
Eosinophilic Granulomatous
Pneumonia
 Brown Norway rats
 Asthma animal model
  bronchiolar responsiveness
  IgE following exposure to allergens
 Pneumonia present w/o experimental
manipulation
 Cause?
Bronchopneumonia
Aspirated Bedding!
2014 CLASS/POLA.Diseases of
Rats.La Perle
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Corneal Dystrophy






F344: 10-15%
Wistar: 53-58%
Punctate to linear opacities
Ca & P w/ less Fe, Zn, Na, Al
Calcific band keratopathy
Anesthesia (ketamine/xylazine)
  blink response  corneal ulceration
 Vasoconstriction  hypoxia
 Ammonia
Retinal Degeneration
 Age-related
photoreceptor attrition
 Light intensity
 Recommended: 325-400
lux
 Environmental & body
temperature
 Exposure time
 +/- cataracts
2014 CLASS/POLA.Diseases of
Rats.La Perle
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Malocclusion
Ringtail
 Ptyalism,
cellulitis,
weight
loss
  humidity (<25%)
 Powdered
diet
 Preweaning rats
 Annular constrictions
 Dry gangrene
Chloral Hydrate Ileus
Auricular Chondropathy
X
 Anesthesia; euthanasia
 IP injections
 Up to 5 weeks postadministration
 Segmental atony and
distention
 Peritonitis and gastric
ulcers
2014 CLASS/POLA.Diseases of
Rats.La Perle
 Genetic susceptibility, 
environmental
temperature, hydration
status, nutrition
Auricular chondritis, cauliflower ear
Bilateral misshapen ears
+/- ear tag  trauma
Degeneration, chondrolysis, cartilage
hyperplasia, osseous metaplasia
 Granulatomatous inflammation
 Humans: relapsing polychondritis




 Multiple sites (hyaline & elastic cartilage)
 Autoantibodies to collagen types II, IX, X
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Neoplastic Lesions
Laboratory Animal Medicine, 2nd Ed.
Pituitary Tumors






Sprague Dawley, Wistar
Age, genetics, diet, breeding
 w/ food restriction, mating
Adenomas > carcinomas
Pars distalis > pars intermedia
Chromophobe, prolactin-producing
  incidence of fibroadenomas?
2014 CLASS/POLA.Diseases of
Rats.La Perle
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Thyroid Gland
 Follicular
 Hyperplasia
 Adenoma
 Microfollicular, macrofollicular, cystic
 Carcinoma
 Metastases to regional LNs, lungs
 C cell
 Focal-diffuse hyperplasia
 Adenoma
 Carcinoma
 Amyloid
2014 CLASS/POLA.Diseases of
Rats.La Perle
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Adrenal Medulla
 F344, M > F
 Environment, strain, endocrinopathies, diet, chemicals
 Lack catecholamine synthesis/release, urinary excretion or
elevated BP
 Basophilic focus  hyperplasia  benign/malignant
 Pheochromocytoma

Chromaffin cells
 Ganglioneuroma

Ganglion, satellite cells, Schwann cells, nerve fibers (>80%)
 Neuroblastoma

Neuroblasts (>80%)
 Complex: mixture (neural component < 80%)
2014 CLASS/POLA.Diseases of
Rats.La Perle
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Pancreatic Islets
 Hyperplasia
 Duct ligation w/ destruction & atrophy of
acinar parenchyma
 Variable numbers of islets affected
 Adenoma
 Insulin > stomatostatin, glucagon,
pancreatic polypeptide
 Carcinoma
 Local/capsular invasion, anaplasia +/- lung
metastases
Multiple Endocrine
Neoplasia (MEN)





Islet cell tumor
Pheochromocytoma
Thyroid follicular adenoma
Thyroid parafollicular (C-cell) adenoma
Pituitary gland, pars distalis basophil
hyperplasia
 TSH, LH/FSH, ACTH
2014 CLASS/POLA.Diseases of
Rats.La Perle
MEN
 MEN1
 Loss of function mutations in Menin
 Parathyroid, gastroenteropancreatic, anterior
pituitary
 MEN2
Gain of function mutations in RET
Adrenal and thyroid medullas
MEN2A: + parathyroid
MEN2B: + mucocutaneous neuromas,
marfanoid habitus
 FMTC




31
Interstitial Cell Tumors
 Leydig cells
 Aged strains
 F344
 Concurrent
hypercalcemia
Mesothelioma
 F344
 2 subtypes in humans and rats (repeated IP
ferric saccharate)
 Epithelioid/epitheliomatous
 10 site = tunica vaginalis of testes
 Papillary growths
 Mesenchymal/sarcomatous
 Cranial abdominal organs
 Invasiveness
 CDKN2A/2B null and amplification of ERBB2
 Look for mesothelioma and interstitial cell tumor
concurrently
2014 CLASS/POLA.Diseases of
Rats.La Perle
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Cytokeratin
Vimentin
2014 CLASS/POLA.Diseases of
Rats.La Perle
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Mammary Gland Tumors
 Males and females!
 Sprague Dawley
 Genetic, dietary, environmental, endocrine
  w/ food restriction, ovariectomy
 Prolactin levels





No retroviruses!
Fibroadenoma >>> carcinoma
Recurrence vs. new tumor(s)
Rarely metastasize
Syngeneic transplantation
Tumors of Skin
& Other Glands
 Zymbal’s gland
 Base of external ear
 Locally invasive
 Not metastatic
 Preputial/clitoral gland
 Locally invasive
 Metastasize to regional LNs and lungs
 Chemically-induced
 Keratoacanthomas
 Up to 8% incidence depending on strain
2014 CLASS/POLA.Diseases of
Rats.La Perle
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Zymbal’s
Gland
Carcinoma
Zymbal’s
Gland
Carcinoma
Preputial
Gland
Carcinoma
Preputial
Gland
Carcinoma
2014 CLASS/POLA.Diseases of
Rats.La Perle
Preputial
Gland
Carcinoma
Keratoacanthoma
35
Large Granular Leukemia
Keratoacanthoma
 F344
 Syngeneic
transplantation
 Spleen  systemic
 No retroviruses
 NK cells
 Leukemia
 Concurrent IMHA,
thrombocytopenia, DIC
 DDX: lymphoma, histiocytic
sarcoma
Toxicological Sciences 99: 3-19, 2007
Nephroblastomas
 Rare except subline of Sprague Dawley –
Upj:TUC[SD]spf.nb
 Genetically predisposed
 14% incidence
 Chemically-induced
 Model for Wilm’s tumor in humans
 3 components
 Blastema
 Stroma
 Immature epithelium forming tubules
 Precursor lesion: intralobar nephroblastematosis
 Embryonal tissue in rat present until d. 7-8
2014 CLASS/POLA.Diseases of
Rats.La Perle
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Veterinary Pathology 36: 379-390, 1999
Veterinary Pathology 36: 379-390, 1999
Granular Cell Tumors
Brain/meningeal: rat, dog, ferret
Horses: lung
PAS+ granules
Positive: vimentin, S-100, 1-antichymotrypsin
 Negative: GFAP, canine leukocyte
antigens




PAS
2014 CLASS/POLA.Diseases of
Rats.La Perle
37
Chordomas
Chordomas
 Intraosseous remnants of notochord
 Lumbosacral/sacrococcygeal > sphenooccipital
 Slow growing, recur, metastasize
 Ferrets > dogs, cats, rats, mink
 Physaliphorous cells




Sprague Dawley, F344
56/115K
M>F 3:1
Paresis, paralysis, megacolon
2014 CLASS/POLA.Diseases of
Rats.La Perle
 Vacuolated, eccentric nucleus
 Cytokeratin + AND vimentin +
 Fibrous trabeculae
 Pools of mucin
 PAS, mucicarmine, alcian blue
 Humans
 Variant = chondroid chordoma
 Spheno-occipital
 Better prognosis
38
References
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






Thank You!
??
[email protected]
614-292-5480
www.vet.osu.edu/CPMPSR
2014 CLASS/POLA.Diseases of
Rats.La Perle
39