RESSALVA
Atendendo solicitação da
autora, o texto completo desta tese
será disponibilizado somente a partir
de 12/08/2026.
UNIVERSIDADE ESTADUAL PAULISTA
“JÚLIO DE MESQUITA FILHO”
INSTITUTO DE BIOCIÊNCIAS – RIO CLARO
unesp
PROGRAMA DE PÓS-GRADUAÇÃO EM ECOLOGIA, EVOLUÇÃO E
BIODIVERSIDADE
ESTADO REDOX E MOBILIZAÇÃO ENERGÉTICA DURANTE RESPOSTA DE
FASE AGUDA EM MORCEGOS DE DIFERENTES HÁBITOS ALIMENTARES
LUCIA VELARDE CABRERA MARTINEZ
Rio Claro – SP
2025
UNIVERSIDADE ESTADUAL PAULISTA
“JÚLIO DE MESQUITA FILHO”
INSTITUTO DE BIOCIÊNCIAS – RIO CLARO unesp
PROGRAMA DE PÓS-GRADUAÇÃO EM ECOLOGIA, EVOLUÇÃO E
BIODIVERSIDADE
ESTADO REDOX E MOBILIZAÇÃO ENERGÉTICA DURANTE RESPOSTA DE
FASE AGUDA EM MORCEGOS DE DIFERENTES HÁBITOS ALIMENTARES
LUCIA VELARDE CABRERA MARTINEZ
Tese apresentada ao Instituto de
Biociências do Câmpus de Rio Claro,
Universidade Estadual Paulista, como
parte dos requisitos para obtenção do
título de Doutor em Ecologia, Evolução e
Biodiversidade.
Orientador: Dr. Ariovaldo Pereira da
Cruz Neto
Coorientador: Dra. Mariella Bontempo
Duca de Freitas
Rio Claro – SP
2025
C117e
Cabrera-Martinez, Lucia Velarde
Estado redox e mobilização energética durante resposta de fase
aguda em morcegos de diferentes hábitos alimentares / Lucia Velarde
Cabrera-Martinez. -- Rio Claro, 2025
78 p. : il., tabs.
Tese (doutorado) - Universidade Estadual Paulista (UNESP),
Instituto de Biociências, Rio Claro
Orientador: Ariovaldo Pereira da Cruz-Neto
Coorientadora: Mariella Bontempo Duca de Freitas
1. Fisiologia animal. 2. Sistema imune inato. 3. Chiroptera. 4.
Biologia redox. 5. Metabolismo energético. I. Título.
Sistema de geração automática de fichas catalográficas da Unesp. Dados fornecidos pelo autor(a).
UNIVERSIDADE ESTADUAL PAULISTA
Câmpus de Rio Claro
Estado redox e mobilização energética durante resposta de fase aguda em morcegos de
diferentes hábitos alimentares
TÍTULO DA TESE:
CERTIFICADO DE APROVAÇÃO
AUTORA: LUCÍA VELARDE CABRERA MARTINEZ
ORIENTADOR: ARIOVALDO PEREIRA DA CRUZ NETO
COORIENTADORA: MARIELLA BONTEMPO DUCA DE FREITAS
Aprovada como parte das exigências para obtenção do Título de Doutora em Ecologia, Evolução e
Biodiversidade, área: Biodiversidade pela Comissão Examinadora:
Prof. Dr. ARIOVALDO PEREIRA DA CRUZ NETO (Participaçao Virtual)
Departamento de Biodiversidade / Unesp - IB Rio Claro
Profa. Dra. JERUSA MARIA DE OLIVEIRA (Participaçao Virtual)
Instituto de Química e Biotecnologia / Universidade Federal de Alagoas
Prof. Dr. FERNANDO RIBEIRO GOMES (Participaçao Virtual)
Departamento Fisiologia / Universidade de São Paulo
Rio Claro, 12 de fevereiro de 2025
Instituto de Biociências - Câmpus de Rio Claro -
Avenida 24 A, , 1515, 13506900
ib.rc.unesp.br/#!/pos-graduacao/secao-tecnica-de-pos/programas/ecologia-e-biodiversidadeCNPJ: 48.031.918/0018-72.
Dedico esta tese ao meu filho, Iberê. Com a
intenção de ser um exemplo de persistência e
dedicação, mas também de respeito e amor
pela ciência e toda forma de vida.
AGRADECIMENTOS
Agradeço ao Prof. Dr. Ariovaldo Pereira da Cruz Neto pela orientação. Por toda
minha formação acadêmica, desde a graduação, mestrado e agora na finalização do
doutorado. Obrigada pela parceria e confiança em mais de uma década!
À minha co-orientadora, Profa. Dra. Mariella Bontempo Duca de Freitas, e a todos
os alunos e corpo técnico do Laboratório de Ecotoxicologia de Quirópteros (LEC), da
Universidade Federal de Viçosa. Sem o auxílio técnico e científico de vocês não teria sido
possível realizar este projeto.
Agradeço a todos que em algum momento me ajudaram nas coletas de campo e
no laboratório, à minha família pelo apoio durante todos estes anos, e também as pessoas
que eu amo, Marcelo, Saulo, Amy, Carlinha, Ana e Gi, sem a escuta e carinho de vocês
teria sido ainda mais difícil.
Agradeço ao meu filho, Iberê. Dono de um sorriso capaz de me animar e encorajar
apesar das dificuldades. Obrigada por fazer parte de minha vida, amo você.
O presente trabalho foi realizado com apoio da Coordenação de Aperfeiçoamento
de Pessoal de Nível Superior - Brasil (CAPES) - Código de Financiamento 001.
O presente trabalho foi realizado com apoio da Fundação de Amparo à Pesquisa
do Estado de São Paulo (FAPESP), Brasil. Processo nº 2014/16320-7. As opiniões,
hipóteses e conclusões ou recomendações expressas neste material são de
responsabilidade do(s) autor(es) e não necessariamente refletem a visão da FAPESP.
RESUMO GERAL
A indução da resposta de fase aguda (RFA) por meio de lipopolissacarídeo (LPS) de
Escherichia coli desencadeia aumento na taxa metabólica e, consequentemente, no gasto
calórico em várias espécies de morcegos. Nesta tese, apresentamos uma introdução geral
destacando os principais indicadores fisiológicos associados à RFA em morcegos e suas
relações com o equilíbrio oxidativo e a mobilização de reservas energéticas — temas
centrais de ambos os capítulos experimentais. No primeiro capítulo, simulamos a RFA
utilizando LPS em morcegos insetívoros (Molossus molossus) e frugívoros (Artibeus
lituratus), e avaliamos seus efeitos na variação da massa corporal, ingestão alimentar,
atividade de leucócitos e mobilização de proteínas, ácidos graxos e glicogênio.
Esperávamos observar maior variação de massa corporal, redução da ingestão alimentar,
aumento na razão neutrófilo-linfócito e menores concentrações de substratos energéticos
em animais desafiados com LPS em comparação aos animais do controle. No entanto,
nossos resultados sugerem que a ativação da RFA não compromete as reservas energéticas
dos morcegos — ao menos sob condições experimentais e em um curto período de tempo.
Em M. molossus, não observamos efeito da RFA na variação da massa corporal nem na
contagem diferencial de leucócitos. Em A. lituratus, os animais tratados com LPS
ganharam massa apenas na noite anterior à injeção; após a injeção, não houve ganho de
massa, e a ingestão alimentar diminuiu progressivamente até o final do experimento.
Além disso, a razão neutrófilo-linfócito aumentou 24 horas após a injeção de LPS, mas
não apresentou variação após 12 horas, nem após a injeção de PBS ao longo do período
experimental. No segundo capítulo, analisamos a biologia redox do fígado e do músculo
peitoral durante a ativação da RFA em morcegos com diferentes dietas. Espécies reativas
são liberadas durante a RFA, e esperávamos detectar maiores concentrações de
antioxidantes ou marcadores de oxidação em animais desafiados em comparação aos
animais do controle — indicando desequilíbrio oxidativo ou aumento na produção de
antioxidantes em resposta a danos oxidativos. Contrariamente às expectativas, não
observamos efeito do tratamento no fígado ou no músculo peitoral. Esses resultados
sugerem que, independentemente do hábito alimentar, a RFA não compromete o
equilíbrio oxidativo nos tecidos analisados durante as horas que seguem o desafio imune.
Com esta tese, concluímos que, embora a RFA retenha características conservadas dentro
de grupos taxonômicos, ela pode variar entre espécies. No entanto, são necessários mais
estudos para determinar se tais variações são atribuídas exclusivamente aos hábitos
alimentares. Além disso, nossos achados sustentam a noção de que a dieta influencia as
concentrações de antioxidantes endógenos em morcegos; ainda assim, nossos dados não
indicam desequilíbrio oxidativo como resultado da ativação da RFA com LPS. Isso sugere
que a suscetibilidade a danos oxidativos causados pela ativação da imunidade inata nas
espécies estudadas não está diretamente associada ao hábito alimentar.
Palavras-chave: resposta imune inata, LPS, reservas energéticas, antioxidantes, estresse
oxidativo, biologia redox.
GENERAL ABSTRACT
The induction of the acute phase response (APR) using lipopolysaccharide (LPS) from
Escherichia coli triggers an increase in metabolic rate and, consequently, caloric
expenditure in several bat species. In this thesis, we present a general introduction
highlighting the main physiological indicators associated with the APR in bats, and their
relationships with oxidative balance and the mobilization of energy reserves—central
themes of both experimental chapters. In the first chapter, we simulated the APR using
LPS in insectivorous (Molossus molossus) and frugivorous (Artibeus lituratus) bats, and
evaluated its effects on body mass variation, food intake, leukocyte activity, and the
mobilization of protein, fatty acids, and glycogen. We expected to observe greater
variation in body mass, reduced food intake, increased neutrophil-to-lymphocyte ratio,
and lower concentrations of energy substrates in LPS-challenged animals compared to
control animals. However, our results suggest that activation of the APR does not
compromise bats' energy reserves—at least under experimental conditions and over a
short period. In M. molossus, we found no effect of the APR on body mass variation or
leukocyte differential count. In A. lituratus, LPS-treated animals only gained body mass
on the night preceding the injection; following the injection, no mass gain was observed,
and food intake progressively decreased until the end of the experiment. Additionally, the
neutrophil-to-lymphocyte ratio increased 24 hours after LPS injection but showed no
variation 12 hours post-injection or following PBS injection throughout the experimental
period. In the second chapter, we analyzed the redox biology of the liver and pectoral
muscle during APR activation in bats with different diets. Reactive species are released
during the APR, and we expected to detect higher concentrations of antioxidants or
oxidative markers in challenged animals compared to controls—indicating either
oxidative imbalance or an upregulation of antioxidant production in response to oxidative
damage. Contrary to our expectations, we observed no treatment effect in either the liver
or pectoral muscle. These results suggest that, regardless of dietary habit, the APR does
not compromise oxidative balance in the analyzed tissues during the hours following
immune challenge. With this thesis, we conclude that while the APR retains conserved
characteristics within taxonomic groups, it may vary between species. However, further
studies are necessary to determine whether such variations are solely attributable to
dietary habits. Additionally, our findings support the notion that diet influences the
concentrations of endogenous antioxidants in bats; nonetheless, our data do not indicate
oxidative imbalance as a result of APR activation with LPS. This suggests that
susceptibility to oxidative damage caused by innate immune activation in the studied
species is not directly associated with dietary habit.
Keywords: innate immune response, LPS, energy reserves, antioxidants, oxidative stress,
redox biology.
TABLE OF CONTENTS
GENERAL INTRODUCTION………………………………………………….……10
Chapter I: The energetic demand of a simulated bacterial infection does not affect energy
reserves in insectivorous and frugivorous bats……………………………….................19
ABSTRACT .................................................................................................................... 19
INTRODUCTION ........................................................................................................... 20
MATERIAL AND METHODS ....................................................................................... 23
RESULTS ........................................................................................................................ 26
DISCUSSION..................................................................................................................31
CONCLUSSIONS………….……………………………………………..……………36
REFERENCES ………..…………………………...….………………..……………...37
CAPÍTULO II: The redox status of the liver and pectoral muscle in bats (Molossus
molossus and Artibeus lituratus) is not affected by a bacterial immune
challenge……………………………………………………………………..................52
ABSTRACT .................................................................................................................... 52
INTRODUCTION ........................................................................................................... 53
MATERIAL AND METHODS ....................................................................................... 56
RESULTS ........................................................................................................................ 57
DISCUSSION..................................................................................................................60
CONCLUSSIONS………….……………………………….…………….……………63
REFERENCES ………..……………….…...…………………………..……………...64
GENERAL CONCLUSION..........................................................................................70
GENERAL REFERENCES…………………………………………………………..71
10
GENERAL INTRODUCTION
The animal immune capacity is an important factor for survival and, consequently,
for the success of populations. The acute phase response (APR) is the first line of defense
and consists of a complex reaction to inflammatory or infectious stimuli, involving
metabolic, immunological, and biochemical changes to restore homeostasis and fight
pathogens. It is triggered by the action of innate immune system cells, such as
macrophages, dendritic cells, and mast cells, which, upon recognizing infections or tissue
injuries, release pro-inflammatory cytokines such as interleukin-1β (IL-1β), interleukin-
6 (IL-6), and tumor necrosis factor-α (TNF-α). (CRAY; ZAIAS; ALTMAN, 2009;
JANEWAY; MEDZHITOV, 2002; MURPHY et al., 2012). These cytokines reach the liver
through the bloodstream, stimulating the production of acute phase proteins (APPs),
which play key roles in innate immunity modulation, acting in inflammation control, and
tissue protection (KNOLLE; GERKEN, 2000; LEMASTERS; JAESCHKE, 2020).
Bats are particularly interesting models to study immune function. They are
reservoirs of diseases that are potentially fatal to other organisms. Thanks to the
combination of evolutionary adaptations in their immune system, metabolism, and
physiology, they can tolerate various infections without developing clinical symptoms.
Besides their flight-related metabolic adaptations, they show a dampened inflammatory
response, constitutively active interferon pathways, reduced virus-induced cell death,
high baseline body temperature and positive selection in genes involved in immunity,
inflammation, and DNA repair as IFN-α, STING, NLRP3 and P53. (ANINDITA et al.,
2015; BROOK; DOBSON, 2015; BRUNET-ROSSINNI; AUSTAD, 2004; FIELD, 2009;
GONZALEZ; BANERJEE, 2022; LUIS et al., 2013; WIBBELT et al., 2010;
WILKINSON; SOUTH, 2002). However, the magnitude of the physiological and
behavioral changes triggered by immune system activation varies considerably among
bat species. In general, it is assumed that the APR imposes a significant energy cost on
organisms. Macrophages, like other immune cells, are nutrient demanding cells as
evidenced by their hypermetabolic state and significant rates of glucose and glutamine
utilization, relative to other cells in the host (NEWSHOLME; NEWSHOLME, 1989).
The increase in resting metabolic rate (RMR) following the experimental induction of the
APR has been reported for some bat species (CABRERA-MARTINEZ; HERRERA;
CRUZ-NETO, 2018; CABRERA-MARTINEZ; HERRERA M.; CRUZ-NETO, 2019;
GUERRERO-CHACÓN et al., 2018; OTÁLORA-ARDILA et al., 2016, 2017; TRIANA-
11
LLANOS et al., 2019). However, some differences in physiological responses associated
with the APR, such as body mass loss, food ingestion, fever and variation in leucocyte
concentrations vary between species (VIOLA; HERRERA; DA CRUZ-NETO, 2022),
and may be attributed to their life-history. These discrepancies highlight the complexity
of the physiological adjustments triggered by immune activation. Here we aim to explore
the primary physiological indicators associated with the APR in bats experimental
physiology, and their relationship with oxidative balance and energy reserve
mobilization—two subjects that will be discus in this study.
1. Sickness anorexia
During the APR, complex alterations occur in the central nervous system (CNS),
which acts as a central regulator of the inflammatory response, coordinating behavioral
and physiological responses to optimize immune function and conserve energy, thereby
promoting survival (LOCHMILLER; DEERENBERG, 2000). Infection induces a
hypermetabolic state to support the heightened activity of the immune system. This
metabolic shift is driven by the increased demand for glucose and glutamine, essential for
sustaining immune function (CROUSER; DORINSKY, 1996; MICHIE, 1996). As a
result, catabolic processes are activated to supply the additional fuel needed by immune
cells and for protein synthesis, making energy reserves crucial for survival (EXTON,
1997; KLASING; JOHNSTONE, 1991; LEGRAND, 2000; TSIGOS et al., 1997; VAN
NIEKERK et al., 2016). In this context, there is growing interest in understanding how
energy availability influences the modulation of immune function. Researchers have
increasingly focused on how the immune system communicates with the CNS to elucidate
why sick animals lose their appetite, since food ingestion in crucial for energy resources
availability. A central focus has been on the cytokines released by activated monocytes
and macrophages, such as IL-1β, IL-6, and TNF-α (EXTON, 1997; JOHNSON, 1998;
LEGRAND, 2000; VAN NIEKERK et al., 2016). These cytokines act on the
hypothalamus, the brain's primary appetite-regulating center, altering the production and
activity of appetite-related neuropeptides, thereby suppressing hunger (CARLTON;
DEMAS; FRENCH, 2012; INGVARTSEN; BOISCLAIR, 2001). In addition to their
direct effects on the hypothalamus, the release of cytokines and other immune mediators
impacts the gut-brain axis. Altered signaling from the gastrointestinal tract, mediated by
12
vagal nerve stimulation, sends satiety signals to the brain, further reducing the desire to
eat (AVIELLO et al., 2021).
While anorexia during the APR may seem counterproductive given the immune
response heightened energy demands, it is considered an adaptive response, designed to
balance the needs of immune function with resource conservation (EXTON, 1997;
JOHNSON, 1998; VAN NIEKERK et al., 2016). By limiting nutrient availability,
anorexia may reduce the resources accessible to pathogens, as well as conserving energy
that would otherwise be allocated to food search and the digestive process (ADAMO et
al., 2010). Nevertheless, the magnitude of food intake reduction should depend on each
species' capacity for glucose regulation and ability to stock and mobilize energy
substrates, which may be associated to their dietary habits, as has been documented in
some bat species (AMARAL et al., 2019; FREITAS et al., 2003, 2005, 2013, 2010;
FREITAS; WELKER; PINHEIRO, 2006).
One common technique used to experimentally induce a bacterial APR is the
administration of LPS (lipopolysaccharide of Escherichia coli), an immunogenic
component of the outer membrane of gram-negative bacteria that causes the release of
proinflammatory cytokines (CRAY, 2012; CRAY; ZAIAS; ALTMAN, 2009). Reduced
food intake during the induction of the APR with LPS has been recorded in some bat
species. A greater decrease in food intake was reported for a fruit‐eating bat (Carollia
perspicillata) challenged with LPS, in relation to control animals (LPS: 85% decrease,
PBS: 30% decrease) (MELHADO; HERRERA M.; DA CRUZ-NETO, 2020). The effect
of LPS on energy balance was considerable since mean food intake when bats were
injected LPS provided 8.85 kJ in contrast to 42.03 kJ obtained after the control injection.
Similar results were reported for the same species in VIOLA et al. (2022).
In a previous work we stimulated an APR with LPS to measure metabolic changes
in Carollia perspicillata (CABRERA-MARTINEZ; HERRERA M.; CRUZ-NETO,
2019). Bats were divided in fed and unfed (24h fasted) groups. Unfed bats started the
experiments with lower body mass than fed bats, independently of season and treatment
(LPS or control), and such difference was maintained until the end of the experiment.
Contrary to our expectations, unfed LPS-treated bats showed similar increases in body
temperature and peak RMR compared to fed LPS-treated bats, despite having started the
experiments with a lower RMR. Therefore, unfed bats exhibited higher metabolic scope
13
and caloric costs, which was likely compensated by the mobilization of energy reserves.
Additionally, food deprivation led to a delayed metabolic response, as indicated by the
longer time required to reach peak RMR values. In another bat species (Myotis vivesi),
fed and food restricted animals showed comparable RMR, total caloric expenditure, and
skin temperature after the LPS challenge, but the metabolic and fever responses were also
delayed in bats on the restricted diet. Additionally, body mass loss after LPS injection was
1.4 times in fed bats compared to the restricted bats (OTÁLORA-ARDILA et al., 2017).
Therefore, the ability of animals to balance energy demands with immune challenges
appears to be influenced by dietary status, species-specific metabolic strategies, and the
severity of the immune stimulus. Further research is needed to better understand how
these mechanisms vary across taxa and ecological contexts, shedding light on the
evolutionary trade-offs that shape immune responses in energy-limited conditions.
2. Pyrogenic response
Fever is an important defense mechanism against pathogens. It consists in a
controlled body temperature increase, initiated by the hypothalamus in response to
pyrogens. By increasing body temperature, fever enhances the effectiveness of
neutrophils and lymphocytes while inhibiting the growth of temperature-sensitive
pathogens (BILBO; NELSON, 2002; EVANS; REPASKY; FISHER, 2015; MARAIS;
MALONEY; GRAY, 2011; MARTIN; WEIL; NELSON, 2008). However, this elevation
in body temperature also accelerates metabolic activity, leading to an increase in the
production of reactive oxygen species (ROS) (GOMES et al., 2018; HOU et al., 2011). A
higher metabolic rate results in greater mitochondrial activity, where ROS are byproducts
of aerobic respiration. As mitochondrial oxygen consumption rises, so does ROS
production. While oxidative stress is often viewed negatively, the ROS produced during
fever play critical roles in host defense, since these reactive molecules are toxic to many
pathogens, aiding in their destruction (HOU et al., 2011). Additionally, ROS act as
messengers, enhancing immune cell recruitment and promoting cytokine production
(LAURIDSEN, 2019). Despite these beneficial roles, a careful balance is necessary, as
excessive ROS can damage host tissues. Lipid peroxidation caused by ROS can
compromise cell membrane integrity, leading to further tissue damage. Moreover, fever
and ROS production may deplete energy reserves, leaving fewer resources available for
the repair of oxidative damage (EL-BELTAGI; MOHAMED, 2013; SU et al., 2019). The
14
increase in body temperature during the APR, however, varies across species and remains
a topic of ongoing research. In bats, unique adaptations are believed to help mitigate the
costs associated with fever. Bats possess elevated levels of antioxidants to counteract the
high ROS production associated with flight, and they exhibit reduced production of pro-
oxidants relative to other animals of similar size and RMR (AUSTAD; FISCHER, 1991;
BRUNET-ROSSINNI, 2004; WILHELM FILHO et al., 2007). Studies have reported the
increase in body temperature following LPS inoculation in the species Myotis vivesi,
Carollia perspicillata, and Rousettus aegyptiacus when challenged during the resting
period (CABRERA-MARTINEZ; HERRERA M.; CRUZ-NETO, 2019; GUERRERO-
CHACÓN et al., 2018; MORENO et al., 2021; OTÁLORA-ARDILA et al., 2016, 2017).
However, in Molossus molossus challenged with LPS at the beginning of the active
period, body temperature did not increase in relation to the control group, but diurnal
body temperature decreased considerably in LPS and control animals (STOCKMAIER et
al., 2015). Bats possess a remarkable ability to enter torpor even in tropical habitats, a
state of controlled hypothermia, which allows them to conserve energy during periods of
food scarcity or unfavorable environmental conditions (AUDET; FENTON, 1988;
BARTELS; LAW; GEISER, 1998; STAWSKI; GEISER, 2010; TEAGUE O’MARA et
al., 2017). In torpor, their body temperature drops significantly, sometimes approaching
ambient environmental temperatures, thereby reducing the energy required to maintain
homeostasis. Additionally, bats can modulate the production of antioxidants to minimize
the return from torpor to normal metabolic state, reducing the oxidative damage caused
by the increase in RMR (WILHELM FILHO et al., 2007). Therefore, the relationship
between fever and hypothermia in bats highlights the complex physiological adaptations
that allow these animals to balance immune responses, energy conservation, and survival
in various environmental contexts. While fever plays a critical role in pathogen defense,
it demands high energy and can lead to oxidative stress. Hypothermia, by contrast, is a
strategy for energy conservation and survival during harsh conditions, but it may reduce
immune function, since many immune reactions, including cytokine production, antibody
synthesis, and pathogen destruction, are temperature-sensitive and function optimally at
normal or slightly elevated body temperatures (BROESSNER et al., 2012; LUO et al.,
2021; PIKULA et al., 2020a). More research is need to understand how bats manage these
contrasting physiological responses provides valuable insight into their ecology and
15
survival strategies, especially as they are exposed to a variety of environmental and
pathogenic challenges.
3. Leukocyte migration
During the APR, the hematopoietic system is activated to meet immunological
demands and repair tissue damage. One key alteration is leukocytosis, characterized by
an increase in white blood cell count, particularly neutrophils (CRAY, 2012; CRAY;
ZAIAS; ALTMAN, 2009). This response is modulated by pro-inflammatory cytokines
that stimulate the production of neutrophils in the bone marrow, and cortisol, which is
released through the activation of the hypothalamic-pituitary-adrenal (HPA) axis. Cortisol
not only promotes the release of neutrophils from the bone marrow but also inhibits their
migration to tissues, thereby temporarily increasing neutrophil count in the blood
(MURPHY et al., 2012). Neutrophils play a crucial role in tissue injury response. They
migrate to the site of damage in response to chemotactic signals, where they engage in
phagocytosis of invading microorganisms and release lytic enzymes and ROS that aid in
pathogen destruction. A commonly used indicator of the activation of the APR and HPA
axis involvement is the neutrophil/lymphocyte ratio (NLR) (CHESLEY; IV, 2011;
SOCORRO FARIA et al., 2016). An increased NLR reflects either an increase in
neutrophils or a reduction in lymphocytes, often attributed to the immunosuppressive
effects of cortisol, which promotes lymphocyte apoptosis and reduces their proliferation
in the bone marrow.
Bats of the species Molossus molossus, Myotis vivesi, Rousettus aegyptiacus,
Carollia perspicillata and Desmodus rotundus treated with LPS, did not show a
significant increase in total white blood cell counts in relation to control animals.
Nevertheless, the variation in NLR differs among bat species. An increase in NLR
following APR activation was reported in fed Myotis myotis (SELTMANN et al., 2022)
and Rousettus aegyptiacus (MORENO et al., 2021); during the pre-migration period in
Pipistrellus nathusii (VOIGT et al., 2020); and in food-deprived Carollia perspicillata
challenged during the resting period (CABRERA-MARTINEZ; HERRERA M.; CRUZ-
NETO, 2019). No effect of LPS on NLR was observed in fed Carollia perspicillata
(CABRERA-MARTINEZ; HERRERA M.; CRUZ-NETO, 2019) or migratory
Pipistrellus nathusii (VOIGT et al., 2020). Additionally, a decrease in NLR was reported
for Carollia perspicillata challenged during the active period (MELHADO; HERRERA
16
M.; DA CRUZ-NETO, 2020). This broad variation in hematological parameters observed
during the inflammatory response has not yet been fully elucidated. However, it can be
inferred that the exposure period (resting or active) to the inflammatory agent, the dose
of LPS, and other factors related to the species' life history may significantly influence
the bacterial response in bats (VIOLA; HERRERA; DA CRUZ-NETO, 2022; VIOLA;
HERRERA M.; CRUZ-NETO, 2024). A common feature across the before mentioned
studies, is the significant individual variation in bat immune responses to LPS injection,
with some individuals showing an increase, decrease, or no change in white blood cell
counts. The increase in neutrophils, is thought to be initially mediated by cortisol, which
mobilizes marginal pool cells from tissues into the bloodstream as part of an immediate
stress response (CRAY, 2012). The dose-dependent increase in the NLR may be attributed
to a corresponding increase in glucocorticoid levels, which modulate neutrophil and
lymphocyte trafficking (DHABHAR, 2002). Additionally, the robust rise in the NLR
during the active phase could be linked to higher baseline glucocorticoid levels during
this period, enhancing immune function when pathogen exposure is expected to peak
(GONG et al., 2015; MARKOWSKA; MAJEWSKI; SKWARŁO-SOŃTA, 2017;
SCHEIERMANN; KUNISAKI; FRENETTE, 2013).
The relationship between leukocytosis and oxidative stress is crucial in
understanding the dynamics of the immune response during the APR. Particularly the
activation of neutrophils, is associated with the production of ROS as part of the immune
system's defense mechanisms. Neutrophils generate ROS to neutralize pathogens, but
excessive or prolonged ROS production can lead to oxidative stress, which in turn may
cause tissue damage and contribute to chronic inflammation (CHELOMBITKO, 2018;
YU et al., 2022). This dual role of neutrophils—defending against pathogens while
potentially causing collateral damage through ROS production—highlights the fine
balance required for effective immune responses without inducing excessive oxidative
damage. In this context, the dynamic changes in the NLR observed during the APR may
serve as a marker for both the immune response and oxidative stress levels, with a high
NLR potentially indicating an elevated risk of oxidative damage. Thus, understanding the
relationship between leukocytosis, oxidative stress, and glucocorticoid signaling is
essential for gaining insights into the immune responses of bats and other species during
inflammatory events.
17
4. Metabolic adjustments
Inflammatory processes are also accompanied by significant metabolic alterations
aimed at meeting the energy and biosynthetic demands of immune cells and regenerating
tissues (SUN et al., 2020). These metabolic changes are regulated by the interplay of
hormones such as cortisol, insulin, and glucagon, along with pro-inflammatory cytokines,
which collectively enhance gluconeogenesis and mobilize fatty acids and amino acids
(BROSNAN, 1999; KRAUS-FRIEDMANN, 1984). Gluconeogenesis is the process by
which glucose is synthesized from non-carbohydrate precursors such as lactate, amino
acids, and glycerol. During the APR, this process is upregulated to supply glucose, the
primary energy source for immune cells. The release of cortisol increases the expression
of gluconeogenic enzymes in the liver (BOLLEN; KEPPENS; STALMANS, 1998;
KNOLLE; GERKEN, 2000; SOON; TORBENSON, 2023). Pro-inflammatory cytokines
also indirectly stimulate gluconeogenesis by promoting the release of amino acids and
glycerol from peripheral tissues, including muscle and adipose tissue (BROSNAN, 1999;
KRAUS-FRIEDMANN, 1984). To conserve glucose for immune cells and the brain,
other tissues utilize fatty acids as their primary energy source (ZHANG et al., 2020). Fatty
acid mobilization occurs through processes like lipolysis and beta-oxidation (POND,
2005; SCHREIBER; ZECHNER, 2014). During lipolysis, hormones such as cortisol and
epinephrine activate hormone-sensitive lipase in adipose tissue, breaking down
triglycerides into glycerol (used in gluconeogenesis) and free fatty acids. Beta-oxidation
occurs in the liver, where free fatty acids are oxidized in mitochondria to generate ATP,
providing metabolic support for the synthesis of APPs (HOUTEN; WANDERS, 2010).
This process also produces ketone bodies, which serve as an alternative energy source for
other tissues. Additionally, proteolysis, primarily occurring in muscle tissue, is stimulated
by cortisol and pro-inflammatory cytokines (SIMMONS et al., 1984). This process
releases amino acids, such as alanine, which are used by the liver as substrates for
gluconeogenesis and the synthesis of APPs (GABAY; KUSHNER, 1999; GRUYS et al.,
2005). These coordinated metabolic adaptations enable the organism to prioritize immune
defense and tissue repair, efficiently redirecting metabolic resources to support the
inflammatory response and recovery processes.
18
Understanding the immune response in bats is crucial, given their unique
ecological roles and diverse physiological adaptations. Despite the growing interest in bat
immunology, we still have many gaps about the physiological mechanisms underlying
their immune response, especially regarding the mobilization of energy substrates during
immune response activation in bats. It is commonly assumed that bats, like other
vertebrates, rely on stored energy reserves when faced with increased energy demands
during immune activation, especially in situations that demand the allocation of energy
to maintain other important physiological functions. Investigating how bats mobilize and
utilize energy substrates in response to immune challenges could provide valuable
insights into their resilience to infection and their ability to cope with metabolic demands.
Filling these knowledge gaps is crucial not only for understanding bat biology but also
for broader ecological and evolutionary implications. Future studies are needed to
investigate the energetic dynamics of immune activation in bats, which could lead to a
more comprehensive understanding of their immune physiology and help inform
conservation efforts, especially as bats face increasing environmental challenges.
70
GENERAL CONCLUSION
In this study, we investigated the impact of the APR on the energy balance of bats,
focusing on differences between two species, one insectivorous and the other frugivorous.
Initially, we hypothesized that immunological challenges would lead to the mobilization
of glycogen, protein, or fatty acid reserves in bats. However, our results demonstrated that
the immune challenge did not compromise the energy balance in Molossus molossus and
Artibeus lituratus. While a combination of immune stimulation and prolonged food
deprivation might reveal glycemic homeostasis mechanisms not detected in our
experimental design, it is important to note that previous studies suggest an adaptation of
the bat immune system to bacterial pathogens. Moreover, our findings are consistent with
earlier research indicating that activation of the APR in response to bacterial antigens
does not pose a significant threat to oxidative balance in both frugivorous and
insectivorous species. Despite the observed differences in antioxidant levels and oxidative
markers between the species, we could not conclude that diet determines bat susceptibility
to oxidative stress, as neither species exhibited significant alterations during the simulated
immune challenge.
Although studies on oxidative responses in bats have increased across various
contexts, important gaps remain. Bats are known to exhibit remarkable longevity relative
to other animals of similar size and metabolic rate, and they display characteristics that
confer increased tolerance to oxidative damage. Nevertheless, the physiological
mechanisms underlying this capacity, as well as how bats manage these challenges at the
molecular level, remain poorly understood. Therefore, the results of this study offer new
insights into the immunological and metabolic processes in bats, suggesting that, despite
the complex interactions among diet, immune response, and oxidative stress, bats are
highly adapted to physiological challenges. However, further research is needed,
particularly into the molecular specificities underpinning their resistance to oxidative
stress and their immune strategies, thus opening new avenues for future investigation.
71
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