Neotrop. Helminthol., 5(1), 2011

2011 Asociación Peruana de Helmintología e Invertebrados Afines (APHIA)

ISSN: 2218-6425 impreso / ISSN: 1995-1043 on line

Resumen

Abstract

ORIGINAL ARTICLE/ ARTÍCULO ORIGINAL

HISTOPATHOLOGICAL FEATURES OF SCHISTOSOMA MANSONI INFECTION IN AKODON

CURSOR (RODENTIA: SIGMODONTINAE)

CARACTERÍSTICAS HISTOPATÓLOGICAS DE LA INFECCIÓN POR SCHISTOSOMA MANSONI

EN AKODON CURSOR (RODENTIA: SIGMODONTINAE)

1,+ 2 2 1

José Roberto Machado-Silva , Rosângela Rodrigues-Silva , Renata Heisler Neves , Michele Costa-Silva , Regina Maria

1 3

Figueiredo de Oliveira ,Arnaldo Maldonado Júnior

1Laboratório Romero Lascasas Porto, Departamento de Microbiologia, Imunologia e Parasitologia, Faculdade de Ciências

2

Médicas, UERJ, Av. Prof. Manuel de Abreu 444 5º andar, Vila Isabel, 20551-170, Rio de Janeiro, RJ, Brazil Laboratório de

Helmintos Parasitos de Vertebrados, Departamento de Helmintologia, Laboratório de Biologia e Parasitologia de Mamíferos

3

Silvestres Reservatórios, Departamento de Medicina Tropical , Instituto Oswaldo Cruz, Av. Brasil 4365, Manguinhos, 21045-

900, Rio de Janeiro, RJ, Brazil Financial support: Faperj, Capes and Fiocruz.

Suggested citation: Machado-Silva, J.R., Rodrigues-Silva, R., Heisler- Neves, R. Costa-Silva, M., de Oliveira F.R.M., Maldonado Jr. A. 2011.

Histopathological features of Schistosoma mansoni infection in Akodon cursor (Rodentia: Sigmodontinae). Neotropical Helminthology,

vol. 5, n° 1, pp. 41- 49.

The Brazilian grass mouse Akodon cursor Winge, 1887 is notably susceptible to both natural and

experimental infection by Schistosoma mansoni Sambon, 1907. This study was concerned with the

histopathological features of the S. mansoni experimental infection. Laboratory-reared mice were

infected with 150 cercariae (BH strain) by subcutaneous route and killed 9 weeks later. Samples of host

tissues, including liver, spleen, intestine and pancreas were collected for histopathological

examination. In this acute infection, tissue involvement was of variable intensity, although exudative

granulomas predominated in all tissues observed. The cellular composition was predominated by

lymphocytes, macrophages and eosinophils and fibroblasts, depending on the individual granuloma

and its developmental stage. Our results showed that A. cursor may provide a useful model for studying

the pathogenesis of schistosomiais mansoni in a wild rodent model.

Keywords: Akodon cursor – experimental infection – histopathology - Schistosoma mansoni - schistosomiasis mansoni.

El ratón de hierba del Brasil Akodon cursor Winge, 1887 es especialmente susceptible a la infección

natural y experimental por Schistosoma mansoni Sambon, 1907. Este estudio está referido a las

características histopatológicas de la infección experimental por S. mansoni. Los ratones criados en

laboratorio fueron infectados con 150 cercarias (cepa BH) por vía subcutánea y sacrificados nueve

semanas más tarde. Las muestras de los tejidos del huésped, incluyendo el hígado, el bazo, el intestino

y el páncreas se recogieron para su examen histopatológico. En esta infección aguda, la participación

del tejido fue de intensidad variable, aunque granulomas exudativos predominaron en todos los tejidos

observados. En la composición celular predominaron los linfocitos, macrófagos y eosinófilos y

fibroblastos, según el granuloma individual y su etapa de desarrollo. Nuestros resultados mostraron

que A. cursor puede proporcionar un modelo útil para estudiar la patogénesis de la schistosomiais

mansoni en un modelo de roedor silvestre.

Palabras clave: Akodon cursor –histopatología – infección experimental – Schistosoma mansoni – schistosomiasis mansoni.

41

INTRODUCTION

Rural environments are of special interest to

public health because of the transmission of

several zoonoses from wildlife to humans

(Rocha et al., 1988; Brandão-Filho et al.,

2003; D'Andrea et al., 2007). Researches

carried out in Brazil have demonstrated that

some species of wild rodents are natural hosts

for Schistosoma mansoni Sambon, 1907 (Rey,

1 9 9 3 ) , w h i c h i s a d r a w b a c k f o r

schistosomiasis control programs (Peralta et

al., 2009). Owing to the importance of this

problem, wild rodents have been bred under

controlled laboratory conditions for

experimental purpose with S. mansoni (Souza

et al., 1992; Maldonado Jr. et al., 1994; Ribeiro

et al., 1998). Once such host-parasite

interactions are better understood in the

laboratory, it will be more feasible to extend

the findings to infected hosts in nature.

The Brazilian grass mouse Akodon cursor

Winge, 1887 (Rodentia: Sigmodontinae)

possesses many qualities which would be

highly desirable in a laboratory animal: it is

capable of breeding successfully under simple

conditions of management and displays good

adaptation to laboratory facilities (Mello &

Ma t hi a s , 19 87 ) . P re v io u s st u di e s

demonstrated natural infection by S. mansoni

(Coelho et al., 1979; Rodrigues-Silva et al.,

1992), whereas develops experimental

infection similar to that in white mice

(Machado-Silva et al., 1991).

Parasites represent an ecologically important

stressor for hosts, which can leads to organ

damage and changes on the physiology of

hosts. The histopathological hallmark of the

schistosomiasis mansoni infection is the

development of granulomas around mature

eggs, which are trapped in liver and intestines

of immunological competent hosts (Cheever et

al., 1998). Laboratory studies have shown that

the hepatic granulomas of both Nectomys

squamipes Brants, 1827 and Calomys callosus

Renger, 1830 were composed of large and

mature macrophages, often with abundant

schistosomal pigment, eosinophilic

granulocytes, lymphocytes and fibroblasts,

characterizing an exudative-macrophage

granuloma type, usually smaller than the

equivalent granuloma type in mouse (Lenzi et

al., 1995; Costa-Silva et al., 2002).

Descriptions of pathological changes have not

been systematized for A.cursor-S.mansoni

experimental model. The aim of this study was

further substantiate our knowledge about this

relationship, which was assessed through

histopathological parameters.

MATERIAL AND METHODS

Schistosomes and experimental hosts

Husbandry

Histopathology and morphometry of S.

mansoni granulomas

The S. mansoni life cycle is maintained

routinely during the past 40 years in

Biomphalaria glabrata Say, 1818 snails and

mice at the Laboratório de Malacologia

(Instituto Oswaldo Cruz, Brasil) and prepared

by exposing infected snails to light for 2 h to

induce shedding of parasites (Freire et al.,

2003). Eight laboratory-bred A. cursor, five-

month-old, obtained from Laboratório de

Biologia e Parasitologia de Mamíferos

Silvestres Reservatórios (Instituto Oswaldo),

were each subcutaneously inoculated with

approximately 150 Schistosoma mansoni (BH

strain) cercariae (Machado-Silva et al., 1991).

All mice were maintained under standard

laboratory conditions. Mice were individually

caged in polypropylene cages (40 x 33 cm)

with stainless steel-screened covers. Animals

fed conventional mice chow (Nuvilab CR1,

Colombo, Paraná, Brazil) and water was ad

libitum. The experiments reported here comply

with the current laws regarding ethical

procedures with investigated animals (Ellery,

1985). All animals procedures were approved

by IBAMA (license number 02022.002062/01-

04).

Infected mice were euthanized at day 63 after

Histopathological features of Schistosoma mansoni Machado-Silva et al.

42

infection by cervical dislocation. The liver,

intestine, pancreas and spleen were removed.

The tissues were processed routinely for

histological preparation, embedded in

paraffin, sectioned at 5 µm thickness, and

stained with hematoxylin and eosin, Lennert's

Giemsa, Silver, Masson's Trichrome and

Picrosirius for collagen plus polarization

microscopy (Lennert, 1978). Periovular

reactions in the liver were classified according

to Hsü et al. (1972) modified by Lenzi et al.

(1998) in: pre-granulomatous stages: weakly

reactive or non-reactive and exudative stages;

granulomatous stages: exudative-productive,

productive and involutional granulomas. The

area, perimeter, major, and minor diameter of

individual granulomas were measured by

computed image analysis (Image Pro-Plus

Media Cybernetics, US), as described

previously (Costa-Silva et al., 2002).

Experimental data were compared by

descriptive statistics or Kruskal-Wallis

(Vieira, 1991). Measurements with p-values

0.05 were considered significantly different.

Statistical analysis

RESULTS

Liver

All mice infected with S. mansoni showed

inflammatory infiltrates and peri-ovular lesions in

the liver (Fig. 1A) in pre-granulomatous stage,

characterized by exudative reaction (80%) and

granulomatous stage characterized by exudative-

productive reaction (15%) and productive reaction

(5%) (Figs. 1B, 1C, 1D). Many granulomas

contained two zones principally made up of

epithelioid cells in the central region near the egg,

surrounded by a peripheral zone consisting of

numerous inflammatory cells, like pigmented and

non pigmented macrophages, neutrophils,

lymphocytes and plasma cells but predominantly

of eosinophils (Figs. 1C, 1D). Two or more

confluent granulomas were often present (Fig. 1E).

Binucleate hepatocyte was seen around lesions

(Figs. 1C, 1D). Focal necrosis was detected in the

hepatic parenchyma (Figs. 1F).

The morphometric analysis of hepatic granulomas

stained with haematoxilin-eosine was: area

(496873485 µm²), major diameter (29913µm),

minor diameter (2099 µm) and perimeter (83936

µm).

Spleen

Histologic examination of the spleen showed

several isolated eggs with viable miracidiae,

but without yet any inflammatory reaction or

with weak reaction (Fig 2A). The organ was

less afflicted by schistosomal infection than the

liver.

Intestine

Mucosa showed intestinal crypts and villi covered

with absortive epithelial cells with some globet

cells secreting mucus. A normal limit was presented

in the intestinal mucosa that was not involved by

the presence of granulomas. The same occur with

villus, crypts and glands (Fig. 2B).

A diffuse inflammatory infiltrate of eosinophils and

mononuclear cells, mainly lymphocytes, was seen

at the mucosa and submucosa layers, but egg

granulomas were most frequently seen in the

submucosa (Figs. 2B, 2C).

Intestine presented a clear predominance of

exudative, exudative-productive stage granulomas

and productive granulomas, as well as several

isolated eggs with viable miracidium, but without

any inflammatory reaction. Granulomas around

eggs containing well-preserved miracidium

showed an acute inflammatory reaction, with

predominance of polymorphonuclear cells,

including eosinophils, and sometimes,

macrophages. The inflammatory reaction was of

the chronic type, with macrophages, fibroblasts and

collagen deposition in varying amounts around

empty eggshells or eggs containing degenerated

miracidia (Figs 2B, 2C, 2D).

Pancreas

Granulomas were in general large, exudative, or

initial exudative-productive, and a few in

productive reactive stage. The cellular composition

of the granulomas of all mice was predominated by

lymphocytes, macrophages and eosinophils and

Neotrop. Helminthol., 5(1), 2011

43

Figure 1. Hepatic infection with Schistosoma mansoni showing various stages of peri-ovular lesions. A: Initial pre-

granulomatous reaction (H&E). B: exudative granuloma (Lennert's Giemsa). C: exudative-productive granuloma (H&E). D:

productive granuloma (H&E). E: confluence between three granulomas (H&E). F: Focal necrosis in hepatic parenchyma

(Masson's trichrome).

fibroblasts depending on the individual granuloma

and its developmental stage (Fig. 2E, 2F).

Inflamatory infiltrate rich in eosinophilis in the

interlobular septa were seen (Fig. 2E). Confluent

granulomas were observed (Fig. 2F).

Histopathological features of Schistosoma mansoni Machado-Silva et al.

44

Figure 2. Photomicrographs of spleen (A), intestine (B, C, D) and pancreas (E, F) showing inflammatory and peri-ovular reaction.

A. Spleen with isolated eggs and viable miracidiae without inflammatory reaction (H&E). B. Intestinal crypts and villi covered

with absortive epithelial cells with some globet cells secreting mucus (Silver stain). C. A diffuse inflammatory infiltrate at the

mucosa and submucosa layers. Egg granulomas were seen in the submucosa (H&E). D. Granuloma around egg containing well-

preserved miracidium showing an acute inflammatory reaction (H&E). E. Granulomas in initial exudative-productive.

Inflamatory infiltrate rich in eosinophilis in the interlobular septa were seen (H&E). F. Pancreas confluent granuloma (Masson's

trichrome).

Neotrop. Helminthol., 5(1), 2011

45

DISCUSSION

It is known that wild animals harbour many types

of parasitic agents (Brandão-Filho et al., 2003; D'

Andrea et al., 2007). Over the past several years,

we have used laboratory-breeding colonies of wild

rodents for parasitological purpose with S. mansoni

(Souza et al., 1992; Maldonado Jr. et al., 1994;

Ribeiro et al., 1998). However, descriptions of

histopathological changes have not been

systematized for A. cursor. However, rodent

models may have their limitations in

parasitological research due to host physiology,

parasite size constraints and a relatively short host

life span. In addition, rodents living in endemic

areas may be infected with several cercariae load.

Egg production is responsible for both life cycle

progression and host immunopathology during

schistosomiasis, This is a dynamic process in

which eggs exploit the host immune response for

egg output (Doenhoff et al., 1986; Lenzi et al.,

1987; Brindley, 2005), whereas infection elicits a

robust cellular inflammation around mature egg

within the host tissue (Andrade, 2009). Gut is the

disposal site of mature eggs, whereas trapped eggs

induce a gastrointestinal pathology (Chatterjee et

al., 2001).

In this study, schistosome and granulomas lodged

within the mucosa and submucosa of the small

intestine, charactering a pre-granulomatous stage

(Lenzi et al., 1998). This acute inflammatory phase

facilitates the passage of the eggs through the

intestinal wall (Lenzi et al., 1987), which might

explains why A. cursor sheds a high number of

fecal eggs (Machado-Silva et al., 1991). In C.

callosus eggs were distributed along all layers of

the intestine, whereas several intestinal nodules

were localized at the interface between external

muscular layer and intestinal serosa (Lenzi et al.,

2002). Also, diffuse eosinophil infiltration in the

mucosal lamina propria and predominance of

macrophages in the granulomas has been reported

(Lenzi et al., 1995). In this study, eosinophils and

mononuclear cells, mainly lymphocytes, were seen

at the mucosa and submucosa layers. In general,

intestinal granulomas were similar to Swiss mice

Schistosome eggs that do not successfully pass

through the intestinal mucosa towards the lumen

are usually carried by the portal vein blood flow to

the liver, where they become trapped due to the

insufficient diameter of the sinusoids (Pearce,

2005). This process leads to marked inflammation,

tissue eosinophilia, collagen deposition, fibrous

expansion of the portal spaces and intrahepatic

portal-vein obstruction (Abath et al., 2006).

Early studies in mouse models demonstrated that

the morphological aspects of hepatic granulomas

vary among different hosts (Cheever et al., 1998)

and time of infection (Andrade, 2009). This study

and others (Andrade & Warren, 1964; Lenzi et al.,

1995; Costa-Silva et al., 2002) demonstrated that

hepatic granulomas were mainly exudative type,

containing neutrophils, lymphocytes and plasma

cells but predominantly eosinophils. In addition,

hepatic granulomas of C. callosus and N.

squamipes are smaller than granulomas from mice

at the same time of infection (Lenzi et al., 1995;

Costa-Silva et al., 2002). In our experimental

design, the morphometric analysis of granulomas

showed that they were smaller than mice (Costa-

Silva et al., 2002).

In the present study, histologic examination of the

spleen did not show important features in the

severity of infection-induced pathology.

Microscopically, well-preserved eggs were found

without around inflammatory reaction or weakly

reactive response. On the other hand, acutely

infected mice showed splenomegaly with

enlargement of the white pulp and splenic cords

with increased cellularity (Andrade & Azevedo,

1987) and diffuse cellular hyperplasia in both the

red and white pulps, accompanied with congestion

of the splenic sinuses (Souza et al., 2009). In

addition, there was a correlation between reactive

spleen changes and liver alterations, during the

acute phase of mice infection (Andrade & Azevedo,

1987). This statement was not herein confirmed

because changes in the liver have not a

repercussion on splenic architecture, which was

normal in appearance. These results suggest that A.

cursor develops distinct pathophysiological

(Lenzi et al.,1987).

Histopathological features of Schistosoma mansoni Machado-Silva et al.

46

alterations in the acute stage of infection, in which

a role for immunoregulatory mechanisms in this

process should be investigated.

Pancreatic involvement during murine

schistosomiasis has also been reported. The early

stage of the acute infection did not evoke histologic

alteration, which was detected soon began egg

oviposition. At this time of infection, pancreatic

granulomas, minimum lobular atrophy and

eosinophilic change in the ductal epithelium was

observed (Lenzi et al., 1989). As infection

progressed, intense lobular atrophy, interlobular

and pseudocapsular inflammatory infiltrate and

edema, periductal fibrosis and decrease in number

of pancreatic islets were detected. Chronically-

infected mice showed severe pancreatitis,

including involvement of the endocrine pancreas

(Lenzi et al., 1989). Previous studies showed that

naturally-infected N. squamipes had a spectrum of

morphological changes ranging from mild lesions

to severe, which was characterized by

granulomatous pancreatitis (Silva & Andrade,

1989).

In our investigation, pancreatic involvement was

of variable intensity, predominating pre-

granulomatous stages, which appears to be in

disagreement with predominance of exudative-

productive granulomas in mouse model (Lenzi et

al., 1989). It has been suggested that the

pathogenesis of pancreatic injury depends mainly

on the embolization of eggs due to the changes

within the portal system after adult worm

maturation and egg oviposition (Lenzi et al., 1989).

Interestingly, our earlier studies have shown that

schistosome egg-laying in A. cursor increased

between 6-8 weeks post-infection (Machado-Silva

et al., 1991).

Additional studies are needed to extend our

findings to chronic infection, where egg-induced

granulomas cause extensive tissue scarring. The

present data, taken together with previously

reported (Machado-Silva et al., 1991) confirm that

the Brazilian grass mouse may provide a useful

model for studying the biology and pathogenesis of

schistosomiasis mansoni.

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Vieira, S. 1991. Introdução à Bioestatística. Rio

de Janeiro: Ed. Campus.

Received February 28, 2011.

Accepted May 13, 2011.

Author for correspondence/ Autor para correspondência:

José Roberto Machado-Silva

Departamento de Microbiologia, Imunologia e

Parasitologia, Faculdade de Ciências Médicas,

Universidade do Estado do Rio de Janeiro. Rua Prof.

Manuel de Abreu, 444/5º andar, Vila Isabel, CEP 20551-

170, Rio de Janeiro, RJ, Brazil.

Telephone and fax: +55-21-2587.6112.

E-mail/Correo electrónico:

machado@uerj.br

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