Co-infections alter the host immune response but how the systemic and local processes at the site of infection interact is still unclear. The majority of studies on co-infections concentrate on one of the infecting species, an immune function or group of cells and often focus on the initial phase of the infection. Here, we used a combination of experiments and mathematical modelling to investigate the network of immune responses against single and co-infections with the respiratory bacterium Bordetella bronchiseptica and the gastrointestinal helminth Trichostrongylus retortaeformis. Our goal was to identify representative mediators and functions that could capture the essence of the host immune response as a whole, and to assess how their relative contribution dynamically changed over time and between single and co-infected individuals. Network-based discrete dynamic models of single infections were built using current knowledge of bacterial and helminth immunology; the two single infection models were combined into a co-infection model that was then verified by our empirical findings. Simulations showed that a T helper cell mediated antibody and neutrophil response led to phagocytosis and clearance of B. bronchiseptica from the lungs. This was consistent in single and co-infection with no significant delay induced by the helminth. In contrast, T. retortaeformis intensity decreased faster when co-infected with the bacterium. Simulations suggested that the robust recruitment of neutrophils in the co-infection, added to the activation of IgG and eosinophil driven reduction of larvae, which also played an important role in single infection, contributed to this fast clearance. Perturbation analysis of the models, through the knockout of individual nodes (immune cells), identified the cells critical to parasite persistence and clearance both in single and co-infections. Our integrated approach captured the within-host immuno-dynamics of bacteria-helminth infection and identified key components that can be crucial for explaining individual variability between single and co-infections in natural populations. Helikar Tomas thelika@unmc.edu University of Nebraska - Lincoln 2013-06-16T09:37:54Z 2016-01-22T07:08:46Z

<span lang="EN-GB">T. retortaeformis</span><span lang="EN-GB"> Larvae (mouse)</span>

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Pro-inflammatory cytokines (mouse) for more info:<div>http://www.ncbi.nlm.nih.gov/mesh/68016207</div>

2015-12-19T22:13:11Z

<span lang="EN-GB">Interleukin\r\n10 in lungs/small intestine (mouse)</span><div><span lang="EN-GB">UniProt AccessionID: </span><a href="http://www.uniprot.org/uniprot/P18893" style="font-size: small; text-decoration: none; font-family: sans-serif; background-color: rgb(255, 255, 255);">P18893</a></div>

2015-12-19T22:13:11Z

Interleukin 5 (mouse)<div>UniProt AccessionID: <a href="http://www.uniprot.org/uniprot/P04401" style="font-size: small; text-decoration: none; font-family: sans-serif; background-color: rgb(255, 255, 255);">P04401</a></div>

2015-12-19T22:13:11Z

<font face="Arial, Verdana" size="2">Epithelial cells in lung/intestine (mouse) for more info:</font><div><font face="Arial, Verdana" size="2">http://www.ncbi.nlm.nih.gov/mesh/68004847</font></div>

2015-12-19T22:13:11Z

Antibody E (mouse)

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<font face="Arial, Verdana" size="2">B-Lymphocytes. See link:</font><div><font face="Arial, Verdana" size="2">http://www.ncbi.nlm.nih.gov/mesh/68001402</font></div>

2015-12-19T22:13:11Z

Interleukin 4 in the small intestines/lungs (mouse)<div>UniProt AccessionID: <a href="http://www.uniprot.org/uniprot/P07750" style="font-size: small; text-decoration: none; font-family: sans-serif; background-color: rgb(255, 255, 255);">P07750</a></div>

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Antibody G (mouse)

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<span lang="EN-GB">T. retortaeformis- a gastrointestinal helmith (mouse)</span>

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<span lang="EN-GB">Interleukin\r\n12 in systemic compartment (mouse)</span>

2015-12-19T22:13:11Z

<span lang="EN-GB">resident\r\neosinophils (mouse) for more info:</span><div><span lang="EN-GB">http://www.ncbi.nlm.nih.gov/mesh/68004804</span></div>

2015-12-19T22:13:11Z

<span lang="EN-GB">Th2\r\ncells in systemic compartment (mouse) for more info:</span><div><span lang="EN-GB">http://www.ncbi.nlm.nih.gov/mesh/68018418</span></div>

2015-12-19T22:13:11Z

<span lang="EN-GB" style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;">Recruited\r\nneutrophils (mouse) for more info:</span><div><span lang="EN-GB"><font face="Arial, Verdana" size="2">http://www.ncbi.nlm.nih.gov/mesh/68009504</font></span></div>

2015-12-19T22:13:11Z

<span lang="EN-GB">Interleukin\r\n4 in systemic compartment (mouse)</span><div><span lang="EN-GB">UniProt AccessionID: </span><a href="http://www.uniprot.org/uniprot/P07750" style="text-decoration: none; font-family: sans-serif; font-size: small; background-color: rgb(255, 255, 255);">P07750</a></div>

2015-12-19T22:13:11Z

<font face="Arial, Verdana" size="2">Dendritic cells in lungs/small intestine, for more info:</font><div><font face="Arial, Verdana" size="2">http://www.ncbi.nlm.nih.gov/mesh/68003713</font></div>

2015-12-19T22:13:11Z

<span lang="EN-GB">recruited\r\neosinophils (mouse) for more info:</span><div><span lang="EN-GB">http://www.ncbi.nlm.nih.gov/mesh/68004804</span></div>

2015-12-19T22:13:11Z

<span lang="EN-GB">Interleukin\r\n13 (mouse)</span><div><span lang="EN-GB">UniProt AccessionID: </span><a href="http://www.uniprot.org/uniprot/P20109" style="text-decoration: none; font-family: sans-serif; font-size: small; background-color: rgb(255, 255, 255);">P20109</a></div>

2015-12-19T22:13:11Z

Antibody A (mouse)

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Dendritic cells in the systemic compartment, more info:<div>http://www.ncbi.nlm.nih.gov/mesh/68003713</div>

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Interferon gamma in lungs/small intestine (mouse)

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Naive T cells (mouse)

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<span lang="EN-GB">total\r\neosinophils (mouse) for more info:</span><div><span lang="EN-GB">http://www.ncbi.nlm.nih.gov/mesh/68004804</span></div>

2015-12-19T22:13:11Z

<span lang="EN-GB" style="font-size:12.0pt;line-height:\r\n115%;font-family:"Times New Roman","serif";mso-fareast-font-family:"Times New Roman";\r\nmso-ansi-language:EN-GB;mso-fareast-language:EN-US;mso-bidi-language:AR-SA">Th2\r\ncells in lungs/small intestine (mouse)</span>

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<span lang="EN-GB">T\r\nhelper cells subtype I in systemic compartment (mouse)</span>

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<span lang="EN-GB">T\r\nhelper cells subtype I in lungs/small intestine (mouse) </span>

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EC positively regulates PIC [1]. IgA negatively regulates PIC [1]. IL10I negatively regulates PIC [1].

<div>IgA is involved in inhibiting pro-inflammatory cytokines [1]</div>

"Both parasite stages activate epithelial cells that lead to the production of pro-inflammatory cytokines" [1]

"IL4 and IL10, produced by Th2 cells, have anti-inflammatory properties and inhibit pro-inflammatory cytokines and neutrophils" [1]

S_4 1 S_18 1 S_2 1

<div>Th2I positively regulates Il10I [1].</div><div><br/></div>

Th2I positively regulates Il10I [1]

S_24 1

EL2 activates IL5 [1]. Th2I activates IL5 [1,2,3,4,5,6,7,8].

EL2 activates IL5 [1]

IL5 is mediated by Th2I [1,2,3,4,5,6,7,8]

S_16 1 S_24 1

AD positively regulates EC [1]. IS positively regulates EC [1].

<span lang="EN-GB">T. retortaeformis</span><span lang="EN-GB"> Larvae activates EC [1].</span>

<span lang="EN-GB">T. retortaeformis activate EC [1].</span>

S_20 1 S_9 1

BC in conjunction with IL13 positively regulate IgE [1]. BC in conjunction with IL4II positively regulate IgE [1].

"The IgE isotype is produced upon signalling from either IL4 or IL13" [1]

Naïve T cell-initiated B cell proliferation stimulated the prompt increase of mucus IgE [1]

S_14 1 S_6 1 S_17 1 S_6 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">T0 positively regulates BC. BC positively regulates itself [1].</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">BC positively regulates itself [1].</span>

S_22 1 S_6 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">IL4II positively regulates IL4I [1].</span>

S_14 1

BC positively regulates IgG [1].

"Naive T cells stimulate clonal expansion of B cells and these lead to the production of antibodies such as IgG" [1]

S_6 1

<div>IS positively regulates AD [1]. AD<span style="font-size: 10pt;"> positively regulates AD [1,2,3].</span><span style="font-size: 10pt;">  </span><span style="font-size: 10pt;">NE negatively regulates AD [1,2,3]. </span><span style="font-size: 10pt;">IgG negatively regulates AD [1]. </span></div>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">IS positively regulates AD [1]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">IgG negatively regulates AD [1]</span>

"Ingested larvae were either killed by eosinophils, in a probabilistic manner, or successfully developed into adults" [1,2,3]

S_9 1 S_8 1 S_13 1 S_20 1 S_8 1 S_13 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">DCII in conjunction with T0 positively regulates IL12II [1]. IL4II negatively regulates IL12II [1].</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">IL4II negatively regulates IL12II [1]</span>

S_19 1 S_22 1 S_14 1

IS positively regulates EL [1,2]. El2 negatively regulates EL [1].

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">"</span><span style="color: rgb(51, 51, 51); font-family: arial, sans-serif; line-height: 18.0049991607666px; background-color: rgb(255, 255, 255);">Infective larvae stimulate IL13 production by resident eosinophils and these recruit additional eosinophils from the progenitor cells in the peripheral blood" [1,2]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">El2 negatively regulates EL [1]</span>

S_20 1 S_16 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">DCII in conjunction with T0 activates Th2II [1]. IL12II inhibites Th2II [1].</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">IL12II inhibites Th2II [1].</span>

S_19 1 S_22 1 S_10 1

<div>PIC in conjunction with AD activate NE [1]. IFNgI positively regulates NE [1]. IL4I negatively regulates NE [1]. IL10I inhibits NE [1].</div>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">PIC in conjunction with AD activate NE [1]</span>

"IL4 contributed to inhibit neutrophils (via the inhibition of the IL12 node)" [1]<div>"IL4 and IL10, produced by Th2 cells, have anti-inflammatory properties and inhibit pro-inflammatory cytokines and neutrophils" [1]</div>

"IL4 and IL10, produced by Th2 cells, have anti-inflammatory properties and inhibit pro-inflammatory cytokines and neutrophils" [1]

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);"> IFNgI positively regulates NE [1]</span>

S_21 1 S_7 1 S_2 1 S_1 1 S_9 1 S_7 1 S_2 1

<div>DCII in conjunction T0 positively regulates IL4II [1]. Th2II positively regulates IL4II [1]. IL12II negatively regulates IL4II [1]. <span style="font-size: 10pt;">EL2 negatively regulates IL4II [1].</span></div><div><br/></div>

"IL4 and IL12 inhibit each other" [1]

EL2 negatively regulates IL4II [1]

<div>"As described for B. bronchiseptica, dendritic cells interact with naïve T cells (T0) leading to the activation of T cell subtypes Th1 and Th2 through the production of IL12 and IL4" [1]</div>

"As described for B. bronchiseptica, dendritic cells interact with naïve T cells (T0) leading to the activation of T cell subtypes Th1 and Th2 through the production of IL12 and IL4" [1]

"Dendritic cells also activated the Th2 cell mediated expression of IL4" [1]

S_16 1 S_19 1 S_22 1 S_10 1 S_12 1 S_10 1

PIC positively regulates DCI [1].

S_1 1

<div>IL5 in conjunction with IgE activates EL2 [1]. <span style="font-size: 10pt;">IL5 in conjunction with IL13 activates EL2 [1].</span></div>

IgE is involved in activating eosinophils [1]

progenitor eosinophils (i.e. resident eosinophils) are modulated by IL5 and IL13 [1]<div>Infective larvae stimulate IL13 production by resident eosinophils and these recruit additional eosinophils from the progenitor cells in the peripheral blood [1,2]</div>

<span style="color: rgb(51, 51, 51); font-family: arial, sans-serif; line-height: 18.0049991607666px; background-color: rgb(255, 255, 255);">progenitor eosinophils (i.e. resident eosinophils) are modulated by IL5 and IL13 [1]</span>

S_5 1 S_3 1 S_17 1 S_3 1

<div>IS and EL in conjunction activate IL13 [1,9]. EL2 positively regulates IL13 [1]. Th2I activates IL13 [1,2,3,4,5,6,7,8]</div>

"Infective larvae stimulate IL13 production by resident eosinophils and these recruit additional eosinophils from the progenitor cells in the peripheral blood" [1,9]

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">EL2 positively regulates IL13 [1]</span>

IL13 is mediated by Th2I [1,2,3,4,5,6,7,8]

I<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">S and EL in conjunction activate IL13 [1,9]</span>

S_16 1 S_24 1 S_11 1 S_20 1

BC activates IgA [1]. IS activates IgA [1].

IS activates IgA [1].

"Naïve T cell-initiated B cell proliferation stimulated the prompt increase of mucus IgA" [1]

S_6 1 S_20 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">DCI positively regulates DCII [1].</span>

S_15 1

DCI positively regulates IFNgI [1,2]. Th1I activates IFNgI [1].

Th1 cells initiated IFNgI response [1].

<span style="color: rgb(51, 51, 51); font-family: arial, sans-serif; line-height: 18.0049991607666px; background-color: rgb(255, 255, 255);">"The initial vigorous expression of IFN? was driven by dendritic cells, probably as an inflammatory response to the infiltration of microflora and bacteria into the damaged mucosa during the establishment of larvae" [1, 2]</span>

S_15 1 S_26 1

DCII positively regulates T0 [1].

"Pro-inflammatory cytokines activate dendritic cells that stimulate naïve T cells (T0)" [1]

S_19 1

EL positively regulates TEL [1]. EL2 positively regulates TEL [1].

EL2 positively regulates TEL [1].

EL positively regulates TEL [1]

S_16 1 S_11 1

Th2II positively regulates Th2I [1].

S_12 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 14.40000057220459px; background-color: rgb(255, 255, 255);">DCII in conjuction with T0 and Il12II positively regulates Th1II [1]. </span>

S_19 1 S_10 1 S_22 1

Th1II positively regulates Th1I [1].

Th1II positively regulates Th1I [1]

S_25 1